The respiratory system comprises the nasal cavity, airways, and lungs, and has the largest surface area exposed to the external environment. It is thus constantly challenged by various stimuli, ranging from odorants, pollutants, toxins, allergens, to viruses, bacteria, and fungi. Prompt detection and appropriate responses to harmful inhalants are critical to maintaining not only the pivotal gas-exchange function of the system but also the overall health or even vitality of an individual. How the host responds to the external challenges and what damages can be inflicted upon the host depend on the types of harmful stimulus, dosage, host genetic background, and immune history (Yunis et al., 2023).

Over the past decades, viral infection has been salient risks to human health. The severe acute respiratory syndrome coronavirus (SARS-CoV-1), and H1N1 influenza A virus and SARS-CoV2 have caused pandemics (Peiris, 2003; Donaldson et al., 2009; Chen et al., 2020). However, it remains elusive how the host and infectious viruses interact and how the host regulates its responses to the invasion. Both under- and over-reactions by the host appear to engender serious consequences.

Recent studies have shown that several types of epithelial cells expressing the chemosensory receptors play important roles in detecting and responding to the external stimuli in the respiratory system (Carey and Lee, 2019; Tizzano and Finger, 2013). Among them is a rare type of microvillous cells, tuft cells (Billipp et al., 2021), which have also been found in a number of tissues, including the gastrointestinal tract, pancreas, respiratory airways and lungs, gallbladder, and thymus (Bezençon et al., 2008; Miller et al., 2018; Montoro et al., 2018; Nevalainen, 1977; Saqui-Salces et al., 2011; DelGiorno et al., 2020). These cells can sense noxious stimuli and invading pathogens, such as allergens, bacteria, protists, and helminths (Gerbe et al., 2016; Howitt et al., 2016; Lei et al., 2018; Luo et al., 2019; von Moltke et al., 2016). Tuft cells are known to express canonical chemosensory signaling pathways, including the sweet and umami taste receptor subunit Tas1r3 (Howitt et al., 2020), bitter taste receptors Tas2rs (Luo et al., 2019; Imai et al., 2020), and olfactory receptors Vmn2r26 (Xiong et al., 2022), as well as their downstream signaling proteins including the heterotrimeric G protein subunits α-gustducin, Gβ1 and Gγ13, phospholipases, and the transient receptor potentialion channel Trpm5 (Howitt et al., 2016; Doyle et al., 2023). Even the signal transduction of the Sucnr1 receptor for succinic acid and free fatty acid receptor 2 Ffar2 for propionate, characteristic metabolites of certain microbes, is mediated by α-gustducin and/or Trpm5 signaling proteins to monitor changes in gut microbiota and airway infection. And ablation of either α-gustducin or Trpm5 diminishes the intestinal and tracheal epithelia’s responses to the infection of the parasitic helminths and microbial colonization (Lei et al., 2018; Nadjsombati et al., 2018; Schneider et al., 2018; Keshavarz et al., 2022; Perniss et al., 2023).

Once stimulated, tuft cells can release a number of output signaling molecules, including IL-25, prostaglandins (Kotas et al., 2022), cysteinyl leukotrienes (Bankova et al., 2018b; Bankova and Boyce, 2018a; McGinty et al., 2020), acetylcholine (Hollenhorst et al., 2020; Krasteva et al., 2011), and other substances, to stimulate type 2 innate lymphoid cells, nerve terminals or adjacent cells, initiating innate and adaptive immune responses, leading to the elimination of irritants and pathogens, and eventually to tissue repair and remodeling (Finger et al., 2003; Tizzano et al., 2010; Saunders et al., 2014). However, tuft cells are heterogeneous in terms of gene expression patterns, signal transduction pathways, and output effectors (Banerjee et al., 2018). For example, some tuft cells express subsets of Tas2r receptors, or cysteinyl leukotriene receptor 3 (Cysltr3) while others do not (Luo et al., 2019; Imai et al., 2020; Bankova et al., 2018b). It seems important to determine ligand profiles, output signals, and physiological roles for tuft cells residing in different tissues to fully understand their protective functions against various pathogens and at different stages of disease progression.

Although they are normally only found in the nasal cavity and trachea, rarely found distal to the lung hilus (Krasteva et al., 2011; Tizzano et al., 2010; Saunders et al., 2014), tuft cells can be ectopically formed in the distal lung following severe viral infection or chemical damage (Rane et al., 2019; Barr et al., 2022; Roach et al., 2022; Melms et al., 2021). These ectopic tuft cells of molecular diversities emerge around 12 days post-viral infection, suggesting that they may not play any role in the initial response to the infection or during viral clearance (Rane et al., 2019; Barr et al., 2022). However, it is unclear whether each subtype of these diverse tuft cells makes unique contributions to the subsequent inflammation resolution, tissue repair, and remodeling. In this study, we conditionally nullified the expression of a heterotrimeric G protein subunit, Gγ13, in the choline acetyltransferase (ChAT)-expressing tuft cells, which resulted in the generation of fewer tuft cells, but conferred even severer injury, slower recovery, and higher fatality following the H1N1 influenza infection. Our data indicate that subsets of ectopic tuft cells with or without Gγ13 expression play different important roles in the inflammation resolution and tissue repair.

Multiple subtypes of tuft cells have been found in various organs, but their distinct functions are not well understood. In this study, we used a conditional gene knockout mouse strain to nullify Gγ13 expression in the ChAT-expressing tuft cells, and found that the number of ectopic tuft cells was reduced in the H1N1 virus-injured lung areas, and all of these remaining tuft cells were Gγ13-negative. Furthermore, the Gng13-cKO mice displayed larger injured areas in the infected lungs, along with heavier immune cell infiltration, severer and prolonged inflammation, increased pyroptosis and cell death, exacerbated lung epithelial leakage and aggravated fibrosis, increased bodyweight loss and heightened fatality. These results imply that the subsets of Gγ13-positive versus negative ectopic tuft cells may play opposite but perhaps balanced roles in the inflammation resolution, tissue repair, and functional recovery, and the absence of Gγ13-positive tuft cells engenders hyper inflammation, consequently leading to aggravated outcomes.

Many signaling proteins are shared by tuft cells and taste receptor cells, including the G protein-coupled Tas1r, and Tas2r receptors (Zhao et al., 2003; Max et al., 2001; Matsunami et al., 2000; Chandrashekar et al., 2000; Adler et al., 2000), the heterotrimeric G protein subunits Gα-gustducin, Gα14, Gβ1, Gβ3, and Gγ13 (Huang et al., 1999; Wong et al., 1996; Tizzano et al., 2008), phospholipase Cβ2 (Plcβ2), and Trpm5. Tuft cells can be deemed as solitary chemosensory cells that are dispersed over many organs of the body, monitoring internal environments, whereas taste receptor cells are aggregated into specialized end organs of taste, taste buds, located in the oral cavity of mammals, evaluating food’s nutritional value or potential toxicity before ingestion (Lindemann, 1996; O’Leary et al., 2019). However, there are some important differences between taste buds and tuft cells. For example, distinct subsets of taste bud cells express Tas1rs and Tas2rs, which are employed to detect high-energy carbohydrates, nutritious amino acids, or potentially harmful and toxic substances, respectively, conveying the chemical information via different gustatory nerve fibers to the central nervous system, generating hedonic sweet and umami taste perception or unpleasant bitter taste (Doyle et al., 2023). In contrast, individual tuft cells can express both Tas1rs and Tas2rs, and the latter are indeed also involved in the detection of infectious microbes and invading parasites that pose risks to the host’s health whereas the function of the former is less clear, and seems to regulate Tas2rs’ signaling or tuft cell homeostasis (Howitt et al., 2020). Results of our present study indicate that Tas2rs expressed by the ectopic tuft cells are also functional, and could be involved in monitoring changes in the extracellular milieu of the injured areas during the switch from the inflammatory response to inflammation resolution, regulating disease progression.

Our results show that ectopic tuft cells first appear around day 12–14 post influenza infection and then the tuft cell number increases over the next two months, which is consistent with a previous report (Rane et al., 2019). However, our study further indicates that the conditional knockout of Gng13 in the ChAT-expressing tuft cells did not affect the generation of dysplastic tuft cells up to 14 days post H1N1 infection, but did decrease ectopic tuft cells’ capability to expand at 20 dpi or later, suggesting that different molecular mechanisms are employed for the initial generation versus subsequent expansion of these tuft cells: the former does not require the contribution from Gγ13-mediated signal transduction whereas the latter does require positive feedback signals released by Gγ13-mediated signaling pathways. It is still unclear how chemically or virally induced major injuries generate these dysplastic tuft cells in the distal lung tissues. Severe injuries can activate quiescent lineage-negative stem/progenitor cells in the pulmonary epithelia via a Notch signaling pathway to proliferate and differentiate into different types of pulmonary epithelial cells to repair and remodel the wounded tissues (Rane et al., 2019; Vaughan et al., 2015). But the exact signals that activate the quiescent stem cells are yet to be identified, although these signals can presumably originate from the apoptotic cells or activated immune cells following the chemical injuries or viral infection. Once activated, the stem/progenitor cells express the transcription factor Pou2f3 at a cell-type specification stage, which has been shown to be critical to the formation of both tuft cells throughout the body and Tas1r- and Tas2r-expressing receptor cells in taste buds, as nullification of the Pou2f3 gene ablates all these taste receptor cells and tuft cells (Gerbe et al., 2016; Matsumoto et al., 2011; Ualiyeva et al., 2020; Yamashita et al., 2017). Pou2f3 may interact with other accessory proteins such as POU domain class 2 associating factors 2 and 3, i.e., Pou2af2 and Pou2af3, respectively, to fine-tune gene expression patterns and direct these cells to differentiate into subtypes of tuft cells or taste receptor cells (Wu et al., 2022). On the other hand, a negative regulatory mechanism has been reported, suggesting that the activating transcription factor 5 (ATF5) appears to inhibit the generation of intestinal tuft cells since more tuft cells were found in the ATF5-deficient ileum (Nakano et al., 2023). Presumably, some intrinsic and extrinsic factors from the severely damaged lung tissues may regulate the activation of Notch, Pou2f3, and ATF5, and together with additional transcription factors such as Gfi1b and Spdef, control the generation of subtypes of ectopic tuft cells in the injured lung.

The proliferation of intestinal tuft cells is dependent on Trpm5 (Howitt et al., 2016; Lei et al., 2018; Luo et al., 2019), but the tracheal tuft cells or sweet, umami, and bitter taste receptor cells in taste buds do not require Trpm5 for their expansion (Damak et al., 2006; Zhang et al., 2003; Finger et al., 2005; Hollenhorst et al., 2022). We and others have found that Trpm5 is not required for the proliferation of the dysplastic pulmonary tuft cells (Barr et al., 2022; Huang, 2022), but conditional nullification of Gng13 ablated part of these ectopic tuft cells and reduced the total number of these cells, indicating that different tuft cells utilize different mechanisms to control their proliferation. In the small intestine, the hyperplasia of tuft cells as well as goblet cells is regulated by the Trpm5-IL25-ILC2-IL13 molecular circuit. Pathogens or microbial metabolites activate the succinate receptor Sucnr1, Tas2rs, Vmn2r26, and prostaglandin receptors and possibly other GPCRs, which then stimulate the heterotrimeric G proteins composed of Gα-gustducin, Gβ1, Gβ3, and Gγ13. Single-cell RNAseq data have shown that many of these GPCRs and G protein subunits are co-expressed in the intestinal as well as ectopic pulmonary tuft cells although additional G protein subunits could also be involved in the signal transduction (Barr et al., 2022). Upon activation, the heterotrimeric Gαβγ dissociates into the Gα and Gβγ13 moieties, each of which can act on their own effectors. While Gα-gustducin’s effectors are still to be determined, Gβγ13 can act on the phospholipase Plcβ2, or other effectors such as adenylate cyclases, phospholipases, receptor kinases, voltage-gated ion channels, and inward rectifying ion channels (Campbell and Smrcka, 2018; Kankanamge et al., 2022). Among them, Plcβ2 can generate the second messengers diacylglycerol (DAG) and inositol trisphosphate (IP3) (Huang et al., 1999). DAG can activate a number of protein kinases, but their eventual physiological effect is yet to be elucidated. On the other hand, IP3 can bind to and open its channel receptor IP3R on the endoplasmic reticulum (ER), releasing the calcium ions from the ER and consequently increasing the cytosolic calcium concentration, leading to the opening of Trpm5, a calcium-activated non-selective monovalent cation channel, depolarizing the membrane potential and releasing certain output signals (Zhang et al., 2007; Liman, 2014). The release of the cytokine IL-25, acetylcholine (ACh), ATP, calcitonin gene-related peptide (CGRP) and component C3 from tuft cells and taste bud cells is dependent on Trpm5, but that of some antimicrobial substances and eicosanoids do not require Trpm5 (Lee et al., 2014), indicating that Trpm5 regulates only some output signals’ release. Since the expansion of ectopic tuft cells is independent of Trpm5, we believe that Trpm5-dependent output signaling molecules may not be involved in the regulation of these tuft cells’ proliferation. On the other hand, the elimination of Gγ13-expressing pulmonary tuft cells in the Gng13-cKO mice suggests that the effectors activated by the Gβγ13 moiety are involved in the regulation of output signals that promote the proliferation of Gγ13-expressing tuft cells. The differential impact of Trpm5 knockout versus Gng13 abolishment on tuft cell proliferation is probably attributed to the fact that Gγ13 is upstream of Trpm5 in the signaling cascades, thus regulating more signaling pathways, and when mutated, having a more profound effects than Trpm5. Further investigation is needed to determine what signals the Gγ13-positive and -negative ectopic pulmonary tuft cells are needed to expand, and with this knowledge, one could intentionally manipulate increasing the clinically beneficial subtypes while decreasing the harmful ones of dysplastic tuft cells.

Previous reports indicate that the elimination of all ectopic tuft cells by knocking out the Pou2f3 gene did not significantly affect the pathogenesis and outcome of H1N1-induced severe injury (Barr et al., 2022; Huang, 2022). In our study, elimination of Gγ13-expressing ectopic pulmonary tuft cells rendered severer symptoms following H1N1 infection, ranging from more immune cell infiltration, increased pyroptotic gene expression and cell death, larger injury areas in the lungs, more BALF protein contents and immune cells, and larger areas of fibrosis, to a slower recovery processes and a higher fatality rate. The striking discrepancy may be caused by the imbalance of tuft cells’ diverse functions in the Gng13-cKO lung. Since the ectopic tuft cells are absent until 12–14 dpi, these cells may not be involved in the initial inflammatory responses to viral infection or the subsequent viral clearance. When the pathogeneses enter the later stages, the Gng13-cKO lungs have a much reduced number of tuft cells with only a few of Gγ13-negative tuft cells remaining, leading to much severer symptoms, indicating that the missing tuft cells may play a major role in the transition from the inflammatory responses to inflammation resolution and subsequent tissue repair processes while the remaining tuft cells are unable to effectively contribute to these processes, or even worse, stimulate inflammation.

Indeed, some tuft cells have been shown to produce pro-inflammatory cytokines and lipid mediators such as IL-25, prostaglandins, and leukotrienes that activate innate and adaptive immune responses (Kotas et al., 2022; Ualiyeva et al., 2021; Hollenhorst and Krasteva-Christ, 2023), and single cell RNAseq analyses indicate that pulmonary ectopic tuft cells express genes that encode enzymes producing specialized pro-resolving mediators (SPMs), for example, Alox5, Alox12e, Alox15, Ptgs2, encoding arachidonate 5-lipoxygenase (5-LOX), arachidonate 12-lipoxygenase (12-LOX), arachidonate 15-lipoxygenase (15-LOX), prostaglandin-endoperoxide synthase II (also known as cyclooxygenase II, COX-2), respectively, as well as the genes encoding various isoforms of cytochrome P450: Cyp51, Cyp2f2, Cyp7b1, and Cyp2j6 (Barr et al., 2022). These enzymes can utilize membrane lipids such as docosahexaenoid acid, eicosapentaenoid acid and arachidonic acid to biosynthesize SPMs, including lipoxins, resolvins, protectins, and maresins, which can limit further infiltration of neutrophils, recruit and stimulate macrophage phagocytosis to remove dead cells and cell debris, suppress the production of pro-inflammatory mediators and cytokines, and increase the production of anti-inflammatory mediators and cytokines, reduce fibrosis and accelerate tissue repair and remodeling (Serhan et al., 2020; Panigrahy et al., 2021; Serhan et al., 2018). So far, the SPMs maresin 1 and resolvin D1 have been shown to inhibit virus- and bacterium-induced inflammation in the lung, respectively (Krishnamoorthy et al., 2023; Codagnone et al., 2018). Together, our data from this study implies that nullification of Gng13 not only significantly reduces the number of ectopic tuft cells but also disrupts the switch from producing proinflammatory lipid mediators to producing anti-inflammatory SPMs. Given the heterogeneity of tuft cells (Xiong et al., 2022; Bankova et al., 2018b; Haber et al., 2017), we hypothesize that the remaining dysplastic tuft cells may continue to produce proinflammatory cytokines and lipid mediators whereas the anti-inflammatory agents-producing tuft cells are absent in the Gng13-cKO mice, consequently leading to severer outcomes.

In conclusion, to our knowledge, it is the first time to postulate that different subtypes of tuft cells may play different subtype-specific roles in the phases of infection, response, resolution, and recovery upon H1N1 infection or other severe injuries. Our data reveal that Gγ13-expressing ectopic tuft cells promote the inflammation resolution and recovery while other dysplastic lung tuft cells contribute to extended inflammation and perhaps immune storms as well.

All data generated or analysed during this study are included in the manuscript and supporting files; source data files have been provided for Figures 1-8.

1. 1. Vaughan AE

   (2022) NCBI Gene Expression Omnibus

   ID GSE197163. Injury-induced pulmonary tuft cells are heterogenous, arise independent of key Type 2 cytokines, and are dispensable for dysplastic repair.

   http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE197163

1. 1. Adler E
   2. Hoon MA
   3. Mueller KL
   4. Chandrashekar J
   5. Ryba NJ
   6. Zuker CS

   (2000) A novel family of mammalian taste receptors

   Cell 100:693–702.

   https://doi.org/10.1016/s0092-8674(00)80705-9

   • PubMed
   • Google Scholar
2. 1. Akbari O
   2. Stock P
   3. Meyer E
   4. Kronenberg M
   5. Sidobre S
   6. Nakayama T
   7. Taniguchi M
   8. Grusby MJ
   9. DeKruyff RH
   10. Umetsu DT

   (2003) Essential role of NKT cells producing IL-4 and IL-13 in the development of allergen-induced airway hyperreactivity

   Nature Medicine 9:582–588.

   https://doi.org/10.1038/nm851

   • Google Scholar
3. 1. Banerjee A
   2. McKinley ET
   3. von Moltke J
   4. Coffey RJ
   5. Lau KS

   (2018) Interpreting heterogeneity in intestinal tuft cell structure and function

   The Journal of Clinical Investigation 128:1711–1719.

   https://doi.org/10.1172/JCI120330

   • PubMed
   • Google Scholar
4. 1. Bankova LG
   2. Boyce JA

   (2018a) A new spin on mast cells and cysteinyl leukotrienes: Leukotriene E4 activates mast cells in vivo

   Journal of Allergy and Clinical Immunology 142:1056–1057.

   https://doi.org/10.1016/j.jaci.2018.08.008

   • Google Scholar
5. 1. Bankova LG
   2. Dwyer DF
   3. Yoshimoto E
   4. Ualiyeva S
   5. McGinty JW
   6. Raff H
   7. von Moltke J
   8. Kanaoka Y
   9. Frank Austen K
   10. Barrett NA

   (2018b) The cysteinyl leukotriene 3 receptor regulates expansion of IL-25-producing airway brush cells leading to type 2 inflammation

   Science Immunology 3:eaat9453.

   https://doi.org/10.1126/sciimmunol.aat9453

   • PubMed
   • Google Scholar
6. 1. Barkauskas CE
   2. Cronce MJ
   3. Rackley CR
   4. Bowie EJ
   5. Keene DR
   6. Stripp BR
   7. Randell SH
   8. Noble PW
   9. Hogan BLM

   (2013) Type 2 alveolar cells are stem cells in adult lung

   The Journal of Clinical Investigation 123:3025–3036.

   https://doi.org/10.1172/JCI68782

   • PubMed
   • Google Scholar
7. 1. Barr J
   2. Gentile ME
   3. Lee S
   4. Kotas ME
   5. Fernanda de Mello Costa M
   6. Holcomb NP
   7. Jaquish A
   8. Palashikar G
   9. Soewignjo M
   10. McDaniel M
   11. Matsumoto I
   12. Margolskee R
   13. Von Moltke J
   14. Cohen NA
   15. Sun X
   16. Vaughan AE

   (2022) Injury-induced pulmonary tuft cells are heterogenous, arise independent of key Type 2 cytokines, and are dispensable for dysplastic repair

   eLife 11:e78074.

   https://doi.org/10.7554/eLife.78074

   • PubMed
   • Google Scholar
8. 1. Bezençon C
   2. Fürholz A
   3. Raymond F
   4. Mansourian R
   5. Métairon S
   6. Le Coutre J
   7. Damak S

   (2008) Murine intestinal cells expressing Trpm5 are mostly brush cells and express markers of neuronal and inflammatory cells

   The Journal of Comparative Neurology 509:514–525.

   https://doi.org/10.1002/cne.21768

   • PubMed
   • Google Scholar
9. 1. Billipp TE
   2. Nadjsombati MS
   3. von Moltke J

   (2021) Tuning tuft cells: new ligands and effector functions reveal tissue-specific function

   Current Opinion in Immunology 68:98–106.

   https://doi.org/10.1016/j.coi.2020.09.006

   • PubMed
   • Google Scholar
10. 1. Campbell AP
    2. Smrcka AV

    (2018) Targeting G protein-coupled receptor signalling by blocking G proteins

    Nature Reviews. Drug Discovery 17:789–803.

    https://doi.org/10.1038/nrd.2018.135

    • PubMed
    • Google Scholar
11. 1. Carey RM
    2. Lee RJ

    (2019) Taste receptors in upper airway innate immunity

    Nutrients 11:2017.

    https://doi.org/10.3390/nu11092017

    • PubMed
    • Google Scholar
12. 1. Chandrashekar J
    2. Mueller KL
    3. Hoon MA
    4. Adler E
    5. Feng L
    6. Guo W
    7. Zuker CS
    8. Ryba NJP

    (2000) T2Rs function as bitter taste receptors

    Cell 100:703–711.

    https://doi.org/10.1016/S0092-8674(00)80706-0

    • Google Scholar
13. 1. Chen G
    2. Wu D
    3. Guo W
    4. Cao Y
    5. Huang D
    6. Wang H
    7. Wang T
    8. Zhang X
    9. Chen H
    10. Yu H
    11. Zhang X
    12. Zhang M
    13. Wu S
    14. Song J
    15. Chen T
    16. Han M
    17. Li S
    18. Luo X
    19. Zhao J
    20. Ning Q

    (2020) Clinical and immunological features of severe and moderate coronavirus disease 2019

    The Journal of Clinical Investigation 130:2620–2629.

    https://doi.org/10.1172/JCI137244

    • PubMed
    • Google Scholar
14. 1. Codagnone M
    2. Cianci E
    3. Lamolinara A
    4. Mari VC
    5. Nespoli A
    6. Isopi E
    7. Mattoscio D
    8. Arita M
    9. Bragonzi A
    10. Iezzi M
    11. Romano M
    12. Recchiuti A

    (2018) Resolvin D1 enhances the resolution of lung inflammation caused by long-term Pseudomonas aeruginosa infection

    Mucosal Immunology 11:35–49.

    https://doi.org/10.1038/mi.2017.36

    • Google Scholar
15. 1. Damak S
    2. Rong M
    3. Yasumatsu K
    4. Kokrashvili Z
    5. Pérez CA
    6. Shigemura N
    7. Yoshida R
    8. Mosinger B
    9. Glendinning JI
    10. Ninomiya Y
    11. Margolskee RF

    (2006) Trpm5 null mice respond to bitter, sweet, and umami compounds

    Chemical Senses 31:253–264.

    https://doi.org/10.1093/chemse/bjj027

    • PubMed
    • Google Scholar
16. 1. DelGiorno KE
    2. Naeem RF
    3. Fang L
    4. Chung C-Y
    5. Ramos C
    6. Luhtala N
    7. O’Connor C
    8. Hunter T
    9. Manor U
    10. Wahl GM

    (2020) Tuft cell formation reflects epithelial plasticity in pancreatic injury: Implications for modeling human pancreatitis

    Frontiers in Physiology 11:88.

    https://doi.org/10.3389/fphys.2020.00088

    • PubMed
    • Google Scholar
17. 1. Donaldson LJ
    2. Rutter PD
    3. Ellis BM
    4. Greaves FEC
    5. Mytton OT
    6. Pebody RG
    7. Yardley IE

    (2009) Mortality from pandemic A/H1N1 2009 influenza in England: public health surveillance study

    BMJ 339:b5213.

    https://doi.org/10.1136/bmj.b5213

    • PubMed
    • Google Scholar
18. 1. Doyle ME
    2. Premathilake HU
    3. Yao Q
    4. Mazucanti CH
    5. Egan JM

    (2023) Physiology of the tongue with emphasis on taste transduction

    Physiological Reviews 103:1193–1246.

    https://doi.org/10.1152/physrev.00012.2022

    • PubMed
    • Google Scholar
19. 1. Finger TE
    2. Böttger B
    3. Hansen A
    4. Anderson KT
    5. Alimohammadi H
    6. Silver WL

    (2003) Solitary chemoreceptor cells in the nasal cavity serve as sentinels of respiration

    PNAS 100:8981–8986.

    https://doi.org/10.1073/pnas.1531172100

    • PubMed
    • Google Scholar
20. 1. Finger TE
    2. Danilova V
    3. Barrows J
    4. Bartel DL
    5. Vigers AJ
    6. Stone L
    7. Hellekant G
    8. Kinnamon SC

    (2005) ATP signaling is crucial for communication from taste buds to gustatory nerves

    Science 310:1495–1499.

    https://doi.org/10.1126/science.1118435

    • Google Scholar
21. 1. Gerbe F
    2. Sidot E
    3. Smyth DJ
    4. Ohmoto M
    5. Matsumoto I
    6. Dardalhon V
    7. Cesses P
    8. Garnier L
    9. Pouzolles M
    10. Brulin B
    11. Bruschi M
    12. Harcus Y
    13. Zimmermann VS
    14. Taylor N
    15. Maizels RM
    16. Jay P

    (2016) Intestinal epithelial tuft cells initiate type 2 mucosal immunity to helminth parasites

    Nature 529:226–230.

    https://doi.org/10.1038/nature16527

    • PubMed
    • Google Scholar
22. 1. Haber AL
    2. Biton M
    3. Rogel N
    4. Herbst RH
    5. Shekhar K
    6. Smillie C
    7. Burgin G
    8. Delorey TM
    9. Howitt MR
    10. Katz Y
    11. Tirosh I
    12. Beyaz S
    13. Dionne D
    14. Zhang M
    15. Raychowdhury R
    16. Garrett WS
    17. Rozenblatt-Rosen O
    18. Shi HN
    19. Yilmaz O
    20. Xavier RJ
    21. Regev A

    (2017) A single-cell survey of the small intestinal epithelium

    Nature 551:333–339.

    https://doi.org/10.1038/nature24489

    • PubMed
    • Google Scholar
23. 1. Halade GV
    2. Kain V
    3. Hossain S
    4. Parcha V
    5. Limdi NA
    6. Arora P

    (2022) Arachidonate 5-lipoxygenase is essential for biosynthesis of specialized pro-resolving mediators and cardiac repair in heart failure

    American Journal of Physiology. Heart and Circulatory Physiology 323:H721–H737.

    https://doi.org/10.1152/ajpheart.00115.2022

    • PubMed
    • Google Scholar
24. 1. Halverson TWR
    2. Wilton M
    3. Poon KKH
    4. Petri B
    5. Lewenza S

    (2015) DNA is an antimicrobial component of neutrophil extracellular traps

    PLOS Pathogens 11:e1004593.

    https://doi.org/10.1371/journal.ppat.1004593

    • PubMed
    • Google Scholar
25. 1. Hollenhorst MI
    2. Jurastow I
    3. Nandigama R
    4. Appenzeller S
    5. Li L
    6. Vogel J
    7. Wiederhold S
    8. Althaus M
    9. Empting M
    10. Altmüller J
    11. Hirsch AKH
    12. Flockerzi V
    13. Canning BJ
    14. Saliba A-E
    15. Krasteva-Christ G

    (2020) Tracheal brush cells release acetylcholine in response to bitter tastants for paracrine and autocrine signaling

    FASEB Journal 34:316–332.

    https://doi.org/10.1096/fj.201901314RR

    • PubMed
    • Google Scholar
26. 1. Hollenhorst MI
    2. Nandigama R
    3. Evers SB
    4. Gamayun I
    5. Abdel Wadood N
    6. Salah A
    7. Pieper M
    8. Wyatt A
    9. Stukalov A
    10. Gebhardt A
    11. Nadolni W
    12. Burow W
    13. Herr C
    14. Beisswenger C
    15. Kusumakshi S
    16. Ectors F
    17. Kichko TI
    18. Hübner L
    19. Reeh P
    20. Munder A
    21. Wienhold S-M
    22. Witzenrath M
    23. Bals R
    24. Flockerzi V
    25. Gudermann T
    26. Bischoff M
    27. Lipp P
    28. Zierler S
    29. Chubanov V
    30. Pichlmair A
    31. König P
    32. Boehm U
    33. Krasteva-Christ G

    (2022) Bitter taste signaling in tracheal epithelial brush cells elicits innate immune responses to bacterial infection

    The Journal of Clinical Investigation 132:e150951.

    https://doi.org/10.1172/JCI150951

    • PubMed
    • Google Scholar
27. 1. Hollenhorst MI
    2. Krasteva-Christ G

    (2023) Chemosensory cells in the respiratory tract as crucial regulators of innate immune responses

    The Journal of Physiology 601:1555–1572.

    https://doi.org/10.1113/JP282307

    • PubMed
    • Google Scholar
28. 1. Howitt MR
    2. Lavoie S
    3. Michaud M
    4. Blum AM
    5. Tran SV
    6. Weinstock JV
    7. Gallini CA
    8. Redding K
    9. Margolskee RF
    10. Osborne LC
    11. Artis D
    12. Garrett WS

    (2016) Tuft cells, taste-chemosensory cells, orchestrate parasite type 2 immunity in the gut

    Science 351:1329–1333.

    https://doi.org/10.1126/science.aaf1648

    • PubMed
    • Google Scholar
29. 1. Howitt MR
    2. Cao YG
    3. Gologorsky MB
    4. Li JA
    5. Haber AL
    6. Biton M
    7. Lang J
    8. Michaud M
    9. Regev A
    10. Garrett WS

    (2020) The taste receptor TAS1R3 regulates small intestinal tuft cell homeostasis

    ImmunoHorizons 4:23–32.

    https://doi.org/10.4049/immunohorizons.1900099

    • PubMed
    • Google Scholar
30. 1. Huang L
    2. Shanker YG
    3. Dubauskaite J
    4. Zheng JZ
    5. Yan W
    6. Rosenzweig S
    7. Spielman AI
    8. Max M
    9. Margolskee RF

    (1999) Gγ13 colocalizes with gustducin in taste receptor cells and mediates IP3 responses to bitter denatonium

    Nature Neuroscience 2:1055–1062.

    https://doi.org/10.1038/15981

    • Google Scholar
31. 1. Huang H

    (2022) Contribution of trp63(creert2)-labeled cells to alveolar regeneration is independent of tuft cells

    eLife 11:e78217.

    https://doi.org/10.7554/eLife.78217

    • Google Scholar
32. 1. Imai H
    2. Hakukawa M
    3. Hayashi M
    4. Iwatsuki K
    5. Masuda K

    (2020) Expression of bitter taste receptors in the intestinal cells of non-human primates

    International Journal of Molecular Sciences 21:902.

    https://doi.org/10.3390/ijms21030902

    • PubMed
    • Google Scholar
33. 1. Jia Q
    2. Cao H
    3. Shen D
    4. Li S
    5. Yan L
    6. Chen C
    7. Xing S
    8. Dou F

    (2019) Quercetin protects against atherosclerosis by regulating the expression of PCSK9, CD36, PPARγ, LXRα and ABCA1

    International Journal of Molecular Medicine 44:893–902.

    https://doi.org/10.3892/ijmm.2019.4263

    • PubMed
    • Google Scholar
34. 1. Kankanamge D
    2. Tennakoon M
    3. Karunarathne A
    4. Gautam N

    (2022) G protein gamma subunit, a hidden master regulator of GPCR signaling

    The Journal of Biological Chemistry 298:102618.

    https://doi.org/10.1016/j.jbc.2022.102618

    • PubMed
    • Google Scholar
35. 1. Keshavarz M
    2. Faraj Tabrizi S
    3. Ruppert A-L
    4. Pfeil U
    5. Schreiber Y
    6. Klein J
    7. Brandenburger I
    8. Lochnit G
    9. Bhushan S
    10. Perniss A
    11. Deckmann K
    12. Hartmann P
    13. Meiners M
    14. Mermer P
    15. Rafiq A
    16. Winterberg S
    17. Papadakis T
    18. Thomas D
    19. Angioni C
    20. Oberwinkler J
    21. Chubanov V
    22. Gudermann T
    23. Gärtner U
    24. Offermanns S
    25. Schütz B
    26. Kummer W

    (2022) Cysteinyl leukotrienes and acetylcholine are biliary tuft cell cotransmitters

    Science Immunology 7:eabf6734.

    https://doi.org/10.1126/sciimmunol.abf6734

    • PubMed
    • Google Scholar
36. 1. Kotas ME
    2. Moore CM
    3. Gurrola JG
    4. Pletcher SD
    5. Goldberg AN
    6. Alvarez R
    7. Yamato S
    8. Bratcher PE
    9. Shaughnessy CA
    10. Zeitlin PL
    11. Zhang IH
    12. Li Y
    13. Montgomery MT
    14. Lee K
    15. Cope EK
    16. Locksley RM
    17. Seibold MA
    18. Gordon ED

    (2022) IL-13-programmed airway tuft cells produce PGE2, which promotes CFTR-dependent mucociliary function

    JCI Insight 7:e159832.

    https://doi.org/10.1172/jci.insight.159832

    • PubMed
    • Google Scholar
37. 1. Krasteva G
    2. Canning BJ
    3. Hartmann P
    4. Veres TZ
    5. Papadakis T
    6. Mühlfeld C
    7. Schliecker K
    8. Tallini YN
    9. Braun A
    10. Hackstein H
    11. Baal N
    12. Weihe E
    13. Schütz B
    14. Kotlikoff M
    15. Ibanez-Tallon I
    16. Kummer W

    (2011) Cholinergic chemosensory cells in the trachea regulate breathing

    PNAS 108:9478–9483.

    https://doi.org/10.1073/pnas.1019418108

    • PubMed
    • Google Scholar
38. 1. Krishnamoorthy N
    2. Walker KH
    3. Brüggemann TR
    4. Tavares LP
    5. Smith EW
    6. Nijmeh J
    7. Bai Y
    8. Ai X
    9. Cagnina RE
    10. Duvall MG
    11. Lehoczky JA
    12. Levy BD

    (2023) The Maresin 1-LGR6 axis decreases respiratory syncytial virus-induced lung inflammation

    PNAS 120:e2206480120.

    https://doi.org/10.1073/pnas.2206480120

    • PubMed
    • Google Scholar
39. 1. Lee RJ
    2. Kofonow JM
    3. Rosen PL
    4. Siebert AP
    5. Chen B
    6. Doghramji L
    7. Xiong G
    8. Adappa ND
    9. Palmer JN
    10. Kennedy DW
    11. Kreindler JL
    12. Margolskee RF
    13. Cohen NA

    (2014) Bitter and sweet taste receptors regulate human upper respiratory innate immunity

    The Journal of Clinical Investigation 124:1393–1405.

    https://doi.org/10.1172/JCI72094

    • PubMed
    • Google Scholar
40. 1. Lei W
    2. Ren W
    3. Ohmoto M
    4. Urban JF
    5. Matsumoto I
    6. Margolskee RF
    7. Jiang P

    (2018) Activation of intestinal tuft cell-expressed Sucnr1 triggers type 2 immunity in the mouse small intestine

    PNAS 115:5552–5557.

    https://doi.org/10.1073/pnas.1720758115

    • PubMed
    • Google Scholar
41. 1. Li F
    2. Ponissery-Saidu S
    3. Yee KK
    4. Wang H
    5. Chen M-L
    6. Iguchi N
    7. Zhang G
    8. Jiang P
    9. Reisert J
    10. Huang L

    (2013) Heterotrimeric G protein subunit Gγ13 is critical to olfaction

    The Journal of Neuroscience 33:7975–7984.

    https://doi.org/10.1523/JNEUROSCI.5563-12.2013

    • PubMed
    • Google Scholar
42. Book

    1. Liman ER

    (2014) Trpm5

    In: Nilius B, Flockerzi V, editors. Handbook of Experimental Pharmacology. Springer. pp. 489–502.

    https://doi.org/10.1007/978-3-642-54215-2_19

    • Google Scholar
43. 1. Lindemann B

    (1996) Taste reception

    Physiological Reviews 76:719–766.

    https://doi.org/10.1152/physrev.1996.76.3.719

    • Google Scholar
44. 1. Lossow K
    2. Hübner S
    3. Roudnitzky N
    4. Slack JP
    5. Pollastro F
    6. Behrens M
    7. Meyerhof W

    (2016) Comprehensive analysis of mouse bitter taste receptors reveals different molecular receptive ranges for orthologous receptors in mice and humans

    The Journal of Biological Chemistry 291:15358–15377.

    https://doi.org/10.1074/jbc.M116.718544

    • PubMed
    • Google Scholar
45. 1. Luo X-C
    2. Chen Z-H
    3. Xue J-B
    4. Zhao D-X
    5. Lu C
    6. Li Y-H
    7. Li S-M
    8. Du Y-W
    9. Liu Q
    10. Wang P
    11. Liu M
    12. Huang L

    (2019) Infection by the parasitic helminth Trichinella spiralis activates a Tas2r-mediated signaling pathway in intestinal tuft cells

    PNAS 116:5564–5569.

    https://doi.org/10.1073/pnas.1812901116

    • PubMed
    • Google Scholar
46. 1. Matsumoto I
    2. Ohmoto M
    3. Narukawa M
    4. Yoshihara Y
    5. Abe K

    (2011) Skn-1a (Pou2f3) specifies taste receptor cell lineage

    Nature Neuroscience 14:685–687.

    https://doi.org/10.1038/nn.2820

    • PubMed
    • Google Scholar
47. 1. Matsunami H
    2. Montmayeur J-P
    3. Buck LB

    (2000) A family of candidate taste receptors in human and mouse

    Nature 404:601–604.

    https://doi.org/10.1038/35007072

    • Google Scholar
48. 1. Max M
    2. Shanker YG
    3. Huang L
    4. Rong M
    5. Liu Z
    6. Campagne F
    7. Weinstein H
    8. Damak S
    9. Margolskee RF

    (2001) Tas1r3, encoding a new candidate taste receptor, is allelic to the sweet responsiveness locus Sac

    Nature Genetics 28:58–63.

    https://doi.org/10.1038/ng0501-58

    • Google Scholar
49. 1. McGinty JW
    2. Ting H-A
    3. Billipp TE
    4. Nadjsombati MS
    5. Khan DM
    6. Barrett NA
    7. Liang H-E
    8. Matsumoto I
    9. von Moltke J

    (2020) Tuft-cell-derived leukotrienes drive rapid anti-helminth immunity in the small intestine but are dispensable for anti-protist immunity

    Immunity 52:528–541.

    https://doi.org/10.1016/j.immuni.2020.02.005

    • PubMed
    • Google Scholar
50. 1. Melms JC
    2. Biermann J
    3. Huang H
    4. Wang Y
    5. Nair A
    6. Tagore S
    7. Katsyv I
    8. Rendeiro AF
    9. Amin AD
    10. Schapiro D
    11. Frangieh CJ
    12. Luoma AM
    13. Filliol A
    14. Fang Y
    15. Ravichandran H
    16. Clausi MG
    17. Alba GA
    18. Rogava M
    19. Chen SW
    20. Ho P
    21. Montoro DT
    22. Kornberg AE
    23. Han AS
    24. Bakhoum MF
    25. Anandasabapathy N
    26. Suárez-Fariñas M
    27. Bakhoum SF
    28. Bram Y
    29. Borczuk A
    30. Guo XV
    31. Lefkowitch JH
    32. Marboe C
    33. Lagana SM
    34. Del Portillo A
    35. Tsai EJ
    36. Zorn E
    37. Markowitz GS
    38. Schwabe RF
    39. Schwartz RE
    40. Elemento O
    41. Saqi A
    42. Hibshoosh H
    43. Que J
    44. Izar B

    (2021) A molecular single-cell lung atlas of lethal COVID-19

    Nature 595:114–119.

    https://doi.org/10.1038/s41586-021-03569-1

    • PubMed
    • Google Scholar
51. 1. Miller CN
    2. Proekt I
    3. von Moltke J
    4. Wells KL
    5. Rajpurkar AR
    6. Wang H
    7. Rattay K
    8. Khan IS
    9. Metzger TC
    10. Pollack JL
    11. Fries AC
    12. Lwin WW
    13. Wigton EJ
    14. Parent AV
    15. Kyewski B
    16. Erle DJ
    17. Hogquist KA
    18. Steinmetz LM
    19. Locksley RM
    20. Anderson MS

    (2018) Thymic tuft cells promote an IL-4-enriched medulla and shape thymocyte development

    Nature 559:627–631.

    https://doi.org/10.1038/s41586-018-0345-2

    • PubMed
    • Google Scholar
52. 1. Montoro DT
    2. Haber AL
    3. Biton M
    4. Vinarsky V
    5. Lin B
    6. Birket SE
    7. Yuan F
    8. Chen S
    9. Leung HM
    10. Villoria J
    11. Rogel N
    12. Burgin G
    13. Tsankov AM
    14. Waghray A
    15. Slyper M
    16. Waldman J
    17. Nguyen L
    18. Dionne D
    19. Rozenblatt-Rosen O
    20. Tata PR
    21. Mou H
    22. Shivaraju M
    23. Bihler H
    24. Mense M
    25. Tearney GJ
    26. Rowe SM
    27. Engelhardt JF
    28. Regev A
    29. Rajagopal J

    (2018) A revised airway epithelial hierarchy includes CFTR-expressing ionocytes

    Nature 560:319–324.

    https://doi.org/10.1038/s41586-018-0393-7

    • PubMed
    • Google Scholar
53. 1. Nadjsombati MS
    2. McGinty JW
    3. Lyons-Cohen MR
    4. Jaffe JB
    5. DiPeso L
    6. Schneider C
    7. Miller CN
    8. Pollack JL
    9. Nagana Gowda GA
    10. Fontana MF
    11. Erle DJ
    12. Anderson MS
    13. Locksley RM
    14. Raftery D
    15. von Moltke J

    (2018) Detection of succinate by intestinal tuft cells triggers a type 2 innate immune circuit

    Immunity 49:33–41.

    https://doi.org/10.1016/j.immuni.2018.06.016

    • PubMed
    • Google Scholar
54. 1. Nakano H
    2. Hata A
    3. Ishimura U
    4. Kosugi R
    5. Miyamoto E
    6. Nakamura K
    7. Muramatsu T
    8. Ogasawara M
    9. Yamada M
    10. Umemura M
    11. Takahashi S
    12. Takahashi Y

    (2023) Activating transcription factor 5 (ATF5) controls intestinal tuft and goblet cell expansion upon succinate-induced type 2 immune responses in mice

    Cell and Tissue Research 393:343–355.

    https://doi.org/10.1007/s00441-023-03781-7

    • Google Scholar
55. 1. Nevalainen TJ

    (1977) Ultrastructural characteristics of tuft cells in mouse gallbladder epithelium

    Cells Tissues Organs 98:210–220.

    https://doi.org/10.1159/000144796

    • Google Scholar
56. 1. O’Leary CE
    2. Schneider C
    3. Locksley RM

    (2019) Tuft cells-systemically dispersed sensory epithelia integrating immune and neural circuitry

    Annual Review of Immunology 37:47–72.

    https://doi.org/10.1146/annurev-immunol-042718-041505

    • PubMed
    • Google Scholar
57. 1. Panigrahy D
    2. Gilligan MM
    3. Serhan CN
    4. Kashfi K

    (2021) Resolution of inflammation: An organizing principle in biology and medicine

    Pharmacology & Therapeutics 227:107879.

    https://doi.org/10.1016/j.pharmthera.2021.107879

    • Google Scholar
58. 1. Peiris JSM

    (2003) Severe Acute Respiratory Syndrome (SARS)

    Journal of Clinical Virology 28:245–247.

    https://doi.org/10.1016/j.jcv.2003.08.005

    • PubMed
    • Google Scholar
59. 1. Perniss A
    2. Boonen B
    3. Tonack S
    4. Thiel M
    5. Poharkar K
    6. Alnouri MW
    7. Keshavarz M
    8. Papadakis T
    9. Wiegand S
    10. Pfeil U
    11. Richter K
    12. Althaus M
    13. Oberwinkler J
    14. Schütz B
    15. Boehm U
    16. Offermanns S
    17. Leinders-Zufall T
    18. Zufall F
    19. Kummer W

    (2023) A succinate/SUCNR1-brush cell defense program in the tracheal epithelium

    Science Advances 9:eadg8842.

    https://doi.org/10.1126/sciadv.adg8842

    • PubMed
    • Google Scholar
60. 1. Rane CK
    2. Jackson SR
    3. Pastore CF
    4. Zhao G
    5. Weiner AI
    6. Patel NN
    7. Herbert DR
    8. Cohen NA
    9. Vaughan AE

    (2019) Development of solitary chemosensory cells in the distal lung after severe influenza injury

    American Journal of Physiology. Lung Cellular and Molecular Physiology 316:L1141–L1149.

    https://doi.org/10.1152/ajplung.00032.2019

    • PubMed
    • Google Scholar
61. 1. Roach SN
    2. Fiege JK
    3. Shepherd FK
    4. Wiggen TD
    5. Hunter RC
    6. Langlois RA

    (2022) Respiratory influenza virus infection causes dynamic tuft cell and innate lymphoid cell changes in the small intestine

    Journal of Virology 96:e0035222.

    https://doi.org/10.1128/jvi.00352-22

    • PubMed
    • Google Scholar
62. 1. Saqui-Salces M
    2. Keeley TM
    3. Grosse AS
    4. Qiao XT
    5. El-Zaatari M
    6. Gumucio DL
    7. Samuelson LC
    8. Merchant JL

    (2011) Gastric tuft cells express DCLK1 and are expanded in hyperplasia

    Histochemistry and Cell Biology 136:191–204.

    https://doi.org/10.1007/s00418-011-0831-1

    • PubMed
    • Google Scholar
63. 1. Saunders CJ
    2. Christensen M
    3. Finger TE
    4. Tizzano M

    (2014) Cholinergic neurotransmission links solitary chemosensory cells to nasal inflammation

    PNAS 111:6075–6080.

    https://doi.org/10.1073/pnas.1402251111

    • PubMed
    • Google Scholar
64. 1. Schneider C
    2. O’Leary CE
    3. von Moltke J
    4. Liang H-E
    5. Ang QY
    6. Turnbaugh PJ
    7. Radhakrishnan S
    8. Pellizzon M
    9. Ma A
    10. Locksley RM

    (2018) A Metabolite-Triggered Tuft Cell-ILC2 circuit drives small intestinal remodeling

    Cell 174:271–284.

    https://doi.org/10.1016/j.cell.2018.05.014

    • PubMed
    • Google Scholar
65. 1. Serhan CN
    2. de la Rosa X
    3. Jouvene CC

    (2018) Cutting edge: Human vagus produces specialized proresolving mediators of inflammation with electrical stimulation reducing proinflammatory eicosanoids

    Journal of Immunology 201:3161–3165.

    https://doi.org/10.4049/jimmunol.1800806

    • PubMed
    • Google Scholar
66. 1. Serhan CN
    2. Gupta SK
    3. Perretti M
    4. Godson C
    5. Brennan E
    6. Li Y
    7. Soehnlein O
    8. Shimizu T
    9. Werz O
    10. Chiurchiù V
    11. Azzi A
    12. Dubourdeau M
    13. Gupta SS
    14. Schopohl P
    15. Hoch M
    16. Gjorgevikj D
    17. Khan FM
    18. Brauer D
    19. Tripathi A
    20. Cesnulevicius K
    21. Lescheid D
    22. Schultz M
    23. Särndahl E
    24. Repsilber D
    25. Kruse R
    26. Sala A
    27. Haeggström JZ
    28. Levy BD
    29. Filep JG
    30. Wolkenhauer O

    (2020) The Atlas of Inflammation Resolution (AIR)

    Molecular Aspects of Medicine 74:100894.

    https://doi.org/10.1016/j.mam.2020.100894

    • PubMed
    • Google Scholar
67. 1. Tizzano M
    2. Dvoryanchikov G
    3. Barrows JK
    4. Kim S
    5. Chaudhari N
    6. Finger TE

    (2008) Expression of Galpha14 in sweet-transducing taste cells of the posterior tongue

    BMC Neuroscience 9:110.

    https://doi.org/10.1186/1471-2202-9-110

    • PubMed
    • Google Scholar
68. 1. Tizzano M
    2. Gulbransen BD
    3. Vandenbeuch A
    4. Clapp TR
    5. Herman JP
    6. Sibhatu HM
    7. Churchill MEA
    8. Silver WL
    9. Kinnamon SC
    10. Finger TE

    (2010) Nasal chemosensory cells use bitter taste signaling to detect irritants and bacterial signals

    PNAS 107:3210–3215.

    https://doi.org/10.1073/pnas.0911934107

    • PubMed
    • Google Scholar
69. 1. Tizzano M
    2. Finger TE

    (2013) Chemosensors in the nose: guardians of the airways

    Physiology 28:51–60.

    https://doi.org/10.1152/physiol.00035.2012

    • PubMed
    • Google Scholar
70. 1. Ualiyeva S
    2. Hallen N
    3. Kanaoka Y
    4. Ledderose C
    5. Matsumoto I
    6. Junger WG
    7. Barrett NA
    8. Bankova LG

    (2020) Airway brush cells generate cysteinyl leukotrienes through the ATP sensor P2Y2

    Science Immunology 5:eaax7224.

    https://doi.org/10.1126/sciimmunol.aax7224

    • PubMed
    • Google Scholar
71. 1. Ualiyeva S
    2. Lemire E
    3. Aviles EC
    4. Wong C
    5. Boyd AA
    6. Lai J
    7. Liu T
    8. Matsumoto I
    9. Barrett NA
    10. Boyce JA
    11. Haber AL
    12. Bankova LG

    (2021) Tuft cell-produced cysteinyl leukotrienes and IL-25 synergistically initiate lung type 2 inflammation

    Science Immunology 6:eabj0474.

    https://doi.org/10.1126/sciimmunol.abj0474

    • PubMed
    • Google Scholar
72. 1. Vaughan AE
    2. Brumwell AN
    3. Xi Y
    4. Gotts JE
    5. Brownfield DG
    6. Treutlein B
    7. Tan K
    8. Tan V
    9. Liu FC
    10. Looney MR
    11. Matthay MA
    12. Rock JR
    13. Chapman HA

    (2015) Lineage-negative progenitors mobilize to regenerate lung epithelium after major injury

    Nature 517:621–625.

    https://doi.org/10.1038/nature14112

    • Google Scholar
73. 1. von Moltke J
    2. Ji M
    3. Liang H-E
    4. Locksley RM

    (2016) Tuft-cell-derived IL-25 regulates an intestinal ILC2–epithelial response circuit

    Nature 529:221–225.

    https://doi.org/10.1038/nature16161

    • Google Scholar
74. 1. Wong GT
    2. Gannon KS
    3. Margolskee RF

    (1996) Transduction of bitter and sweet taste by gustducin

    Nature 381:796–800.

    https://doi.org/10.1038/381796a0

    • Google Scholar
75. 1. Wu XS
    2. He X-Y
    3. Ipsaro JJ
    4. Huang Y-H
    5. Preall JB
    6. Ng D
    7. Shue YT
    8. Sage J
    9. Egeblad M
    10. Joshua-Tor L
    11. Vakoc CR

    (2022) OCA-T1 and OCA-T2 are coactivators of POU2F3 in the tuft cell lineage

    Nature 607:169–175.

    https://doi.org/10.1038/s41586-022-04842-7

    • Google Scholar
76. 1. Xi R
    2. Montague J
    3. Lin X
    4. Lu C
    5. Lei W
    6. Tanaka K
    7. Zhang YV
    8. Xu X
    9. Zheng X
    10. Zhou X
    11. Urban JF
    12. Iwatsuki K
    13. Margolskee RF
    14. Matsumoto I
    15. Tizzano M
    16. Li J
    17. Jiang P

    (2021) Up-regulation of gasdermin C in mouse small intestine is associated with lytic cell death in enterocytes in worm-induced type 2 immunity

    PNAS 118:e2026307118.

    https://doi.org/10.1073/pnas.2026307118

    • PubMed
    • Google Scholar
77. 1. Xiong Z
    2. Zhu X
    3. Geng J
    4. Xu Y
    5. Wu R
    6. Li C
    7. Fan D
    8. Qin X
    9. Du Y
    10. Tian Y
    11. Fan Z

    (2022) Intestinal Tuft-2 cells exert antimicrobial immunity via sensing bacterial metabolite N-undecanoylglycine

    Immunity 55:686–700.

    https://doi.org/10.1016/j.immuni.2022.03.001

    • PubMed
    • Google Scholar
78. 1. Yamashita J
    2. Ohmoto M
    3. Yamaguchi T
    4. Matsumoto I
    5. Hirota J

    (2017) Skn-1a/Pou2f3 functions as a master regulator to generate Trpm5-expressing chemosensory cells in mice

    PLOS ONE 12:e0189340.

    https://doi.org/10.1371/journal.pone.0189340

    • PubMed
    • Google Scholar
79. 1. Yunis J
    2. Short KR
    3. Yu D

    (2023) Severe respiratory viral infections: T-cell functions diverging from immunity to inflammation

    Trends in Microbiology 31:644–656.

    https://doi.org/10.1016/j.tim.2022.12.008

    • PubMed
    • Google Scholar
80. 1. Zhang Y
    2. Hoon MA
    3. Chandrashekar J
    4. Mueller KL
    5. Cook B
    6. Wu D
    7. Zuker CS
    8. Ryba NJP

    (2003) Coding of sweet, bitter, and umami tastes: different receptor cells sharing similar signaling pathways

    Cell 112:293–301.

    https://doi.org/10.1016/s0092-8674(03)00071-0

    • PubMed
    • Google Scholar
81. 1. Zhang Z
    2. Zhao Z
    3. Margolskee R
    4. Liman E

    (2007) The transduction channel TRPM5 is gated by intracellular calcium in taste cells

    The Journal of Neuroscience 27:5777–5786.

    https://doi.org/10.1523/JNEUROSCI.4973-06.2007

    • PubMed
    • Google Scholar
82. 1. Zhao GQ
    2. Zhang Y
    3. Hoon MA
    4. Chandrashekar J
    5. Erlenbach I
    6. Ryba NJP
    7. Zuker CS

    (2003) The receptors for mammalian sweet and umami taste

    Cell 115:255–266.

    https://doi.org/10.1016/s0092-8674(03)00844-4

    • PubMed
    • Google Scholar
83. 1. Zhao G
    2. Weiner AI
    3. Neupauer KM
    4. de Mello Costa MF
    5. Palashikar G
    6. Adams-Tzivelekidis S
    7. Mangalmurti NS
    8. Vaughan AE

    (2020) Regeneration of the pulmonary vascular endothelium after viral pneumonia requires COUP-TF2

    Science Advances 6:eabc4493.

    https://doi.org/10.1126/sciadv.abc4493

    • PubMed
    • Google Scholar

Author details

1. Yi-Hong Li

   College of Life Sciences, Zhejiang University, Hangzhou, China

   Contribution

   Conceptualization, Data curation, Formal analysis, Validation, Investigation, Visualization, Methodology, Writing – original draft

   Competing interests

   No competing interests declared

2. Yi-Sen Yang

   College of Life Sciences, Zhejiang University, Hangzhou, China

   Contribution

   Formal analysis, Investigation, Visualization, Methodology, Writing – original draft

   Competing interests

   No competing interests declared

3. Yan-Bo Xue

   College of Life Sciences, Zhejiang University, Hangzhou, China

   Contribution

   Formal analysis, Validation, Investigation, Visualization, Methodology

   Competing interests

   No competing interests declared

4. Hao Lei

   College of Life Sciences, Zhejiang University, Hangzhou, China

   Contribution

   Data curation, Investigation, Visualization, Methodology

   Competing interests

   No competing interests declared

5. Sai-Sai Zhang

   College of Life Sciences, Zhejiang University, Hangzhou, China

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

6. Junbin Qian

   1. Zhejiang Provincial Key Laboratory of Precision Diagnosis and Therapy for Major Gynecological Diseases, Women’s Hospital, Zhejiang University School of Medicine, Hangzhou, China
   2. Institute of Genetics, Zhejiang University School of Medicine, Hangzhou, China
   3. Cancer Center, Zhejiang University, Hangzhou, China

   Contribution

   Investigation, Visualization

   Competing interests

   No competing interests declared

7. Yushi Yao

   Institute of Immunology and Sir Run Run Shaw Hospital, Zhejiang University School of Medicine, Hangzhou, China

   Contribution

   Investigation, Methodology

   Competing interests

   No competing interests declared

8. Ruhong Zhou

   1. College of Life Sciences, Zhejiang University, Hangzhou, China
   2. Zhejiang University Shanghai Institute for Advanced Study, Shanghai, Shanghai, China

   Contribution

   Conceptualization, Supervision, Funding acquisition, Writing - review and editing

   For correspondence

   rhzhou@zju.edu.cn

   Competing interests

   No competing interests declared

9. Liquan Huang

   1. College of Life Sciences, Zhejiang University, Hangzhou, China
   2. Zhejiang University Shanghai Institute for Advanced Study, Shanghai, Shanghai, China
   3. Monell Chemical Senses Center, Philadelphia, United States

   Contribution

   Conceptualization, Resources, Data curation, Formal analysis, Supervision, Funding acquisition, Validation, Visualization, Methodology, Writing – original draft, Project administration, Writing - review and editing

   For correspondence

   huangliquan@zju.edu.cn

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3400-0685

• 673

  views

• 106

  downloads

• 0

  citations

Views, downloads and citations are aggregated across all versions of this paper published by eLife.