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.

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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

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