Respiratory viral infections cause significant global disease burden with influenza, or flu, being responsible for a significant portion. An estimated 1 billion cases of influenza occur annually resulting in approximately 3–5 million severe cases and 290,000–650,000 deaths (WHO, 2018). In addition to seasonal epidemics caused by both influenza A or B virus (IAV and IBV, respectively), IAV can also cause pandemics. The majority of infections remain asymptomatic or develop mild to moderate respiratory disease, characterized by fever, nasal congestion, cough, and muscle aches. Severe disease mainly affects infants, pregnant women, and the elderly or immunocompromised, but can also occur in otherwise healthy individuals (Cole et al., 2017; Oshansky et al., 2014). The determinants of disease severity are still incompletely understood but may include properties of the virus, environmental factors, genetics, and immune responses of the patient (Kuiken and Taubenberger, 2008; Kuiken et al., 2010). Other agents causing an influenza-like illness (ILI) during influenza season include respiratory syncytial virus (RSV) and seasonal coronaviruses (OC43, HKU1, 229E, and NL63). Similar to IAV, coronaviruses are capable of causing pandemics, most notably the ongoing coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) (Zhou et al., 2020).

IAV is primarily transmitted via inhalation of virus-containing aerosols or droplets, and mainly targets respiratory epithelial cells (Tellier, 2006; Sanders et al., 2011), with the nasopharynx being the initial site of virus replication. IAV generally remains localized to the airways, despite signs of systemic inflammation (Stramer et al., 2012). At the site of infection, resident innate immune cells including monocytes and dendritic cells (DCs) rapidly respond to the presence of virus by secreting cytokines, interferons, and chemokines to limit viral spread and recruit immune cells (Sakabe et al., 2011; Wang et al., 2012). Monocytes and DCs shape the specificity and strength of the subsequent adaptive responses (Kwissa et al., 2014; Spörri and Reis e Sousa, 2005). In blood, three subsets of monocytes are found: the CD14+CD16– classical monocytes (CMs), the most frequent subset at steady state; the terminally differentiated CD14–CD16+ nonclassical monocytes (NCMs); and CD14+CD16+ intermediate monocytes (IMs) that represent CMs transitioning into NCMs (Boyette et al., 2017; Jakubzick et al., 2013; Patel et al., 2017). Blood IMs are readily identifiable at steady state and expand rapidly in response to inflammation, infection, or vaccination (Oshansky et al., 2014; Kwissa et al., 2014; Fingerle et al., 1993). In addition, monocytes extravasate to tissue where they play an important role in innate immune protection. Monocytes also secrete TNFα, a major regulator of innate immune function that is central to the cytokine storm associated with IAV infection (Tisoncik et al., 2012). Conventionally, DCs were grouped as the CD1c+ myeloid DCs (MDCs) that excel at activating naïve T cells Hémont et al., 2013; the CD141+ MDCs that can efficiently can cross-present antigens via MHC-I Jongbloed et al., 2010; and the CD123+ plasmacytoid DCs (PDCs) that mediate type I IFN responses (Cella et al., 1999). More recent single-cell sequencing and unbiased clustering revealed six subtypes of DCs and four subtypes of monocytes (Villani et al., 2017). In this manuscript, we focus on cDC1 (previously CD141+ MDCs) and cDC2 (previously CD1c+ MDCs). We also speculate the roles for DC3s (inflammatory CD14-expressing CD1c+ MDCs, which seemingly arise in a GM-CSF-dependent manner) (Bourdely et al., 2020) and pre-DCs (AXL+SIGLEC6+CD11c^lowCD123+DCs that do not produce IFNα upon TLR9 stimulation but produce IL-12p70 at levels comparable to cDCs) (Villani et al., 2017; See et al., 2017). Monocytes and DCs vary in distribution and function, depending on the anatomical compartment (Baharom et al., 2016; Alcántara-Hernández et al., 2017). Moreover, monocytes and DCs are susceptible to IAV infection in vitro, and the cytopathic nature of the virus may impair their antigen processing and presenting functions (Smed-Sörensen et al., 2012; Diao et al., 2014; Baharom et al., 2015), delaying recovery and normalization of immune cell distribution and function (Jochems et al., 2018; Lichtner et al., 2011).

Studies have shown that monocytes and DCs are recruited to the nasopharynx following infection with 2009 H1N1pdm IAV strains (Oshansky et al., 2014), and in individuals hospitalized with severe influenza infections (Gill et al., 2008; Gill et al., 2005). Disease severity in hospitalized patients has been shown to correlate with (1) monocyte recruitment and increased levels of MCP3, IFNα-2, and IL-10 in the nasal compartment (Oshansky et al., 2014) and (2) strong TNF-producing monocytic responses in blood (Cole et al., 2017) and inflammatory, neutrophil-dominant patterns (Dunning et al., 2018). Despite accounting for a comparatively greater burden of disease, immune responses during mild seasonal influenza infections remain less studied. Therefore, the roles played by monocytes and DCs in contributing to or mitigating mild influenza disease are largely unknown. Additionally, while the response of blood monocytes and DCs to IAV has been studied well in vitro and in animal models (Smed-Sörensen et al., 2012; Diao et al., 2014; Jochems et al., 2018; Vangeti et al., 2019; McGill et al., 2008; Mount and Belz, 2010; GeurtsvanKessel et al., 2008), few studies compare responses between blood and the nasopharynx in human infections (Dunning et al., 2018; Vangeti et al., 2019; Segura et al., 2013). Immune cell behaviour in the nasopharynx during IBV and RSV infections has not been studied in great detail but evidence of DC mobilization to the nasal cavity has been reported (Gill et al., 2008). Studies on immune responses to mild SARS-CoV-2 infection have also primarily focused on blood and rarely the upper airways (Mick et al., 2020).

Here, we determined monocyte and DC subset distribution, maturation and function in both blood and, for the first time, the nasopharynx, in patients with mild to moderate seasonal influenza and influenza-like infections. The methods described in this study allowed us to investigate airway immunity in a larger cohort of patients with SARS-CoV-2 infection (Falck-Jones et al., 2021; Cagigi et al., 2021), showing that methods to study the immune responses in the nasopharynx during acute disease are essential tools as we face the possibility of future pandemics. Comparing the dynamics of systemic and nasopharyngeal immune function will add to our understanding of the roles of monocytes and DCs in shaping the nature and magnitude of inflammation and subsequently disease severity during respiratory viral infections.

In this study, we mapped monocyte and DC distribution and function in blood and in the nasopharynx (the initial site of infection) of patients with ongoing IAV, IBV, RSV, or SARS-CoV-2 infections and in HCs. Several studies have examined immune responses during severe influenza, in particular, focusing on patients sampled during or immediately following the 2009 H1N1 pandemic (Cole et al., 2017; Oshansky et al., 2014; Dunning et al., 2018; Marion et al., 2016), or patients hospitalized with severe respiratory symptoms (Cole et al., 2017; Gill et al., 2008; Gill et al., 2005; Dunning et al., 2018; Marion et al., 2016); and more recently, the immune dysregulation during severe COVID-19 (Zingaropoli et al., 2021; Del Valle et al., 2020; Merad and Martin, 2020; Mudd et al., 2020). Here, we elucidated the innate myeloid cell composition and responses in a cohort with relatively mild symptoms, advanced age, and underlying comorbidities, typical of seasonal influenza. Finally, we showed that our methods can be adapted to study immune responses in other viral infections, including the current COVID-19 pandemic.

Flow cytometric characterization revealed an influx of monocytes and DCs to the nasopharynx during infection, in line with previous reports in more severe IAV patients (Oshansky et al., 2014; Gill et al., 2008; Gill et al., 2005; Herold et al., 2006). Interestingly, age appeared to differentially skew the CD14+CD16+ IM response in IAV patients. Despite having higher baseline frequencies of circulating CD16-expressing monocytes (The Milieu Intérieur Consortium et al., 2018), older patients have fewer CD14+CD16+ IMs in blood during acute IAV infection and concurrently more IMs in the nasopharynx. The increase in IMs suggests a more inflammatory milieu at the site of infection in older patients, perhaps contributing to disease severity as previously suggested in pandemic influenza (Cole et al., 2017; Oshansky et al., 2014; Kuiken and Taubenberger, 2008; Kuiken et al., 2010). Despite the general increase in CD14+CD16+ IM frequencies, CD14+CD16– CMs remained the most frequent monocyte/DC subset in either compartment implying a functional role for CMs during IAV infection. Similar to studies in paediatric patients (Gill et al., 2008; Gill et al., 2005), we also found that over the course of the illness, DCs appeared to migrate from blood to infiltrate the nasopharynx. However, older patients displayed a weaker recruitment of CD1c+ MDCs. In vitro studies have shown that monocytes can differentiate into type I IFN producing mo-DCs in response to IAV exposure (Cao et al., 2012). It is therefore possible that CMs recruited to the nasopharynx in older individuals preferentially differentiate into IMs rather than mo-DCs. Moreover, cDC2 function is critical for clearance of IAV infection (GeurtsvanKessel et al., 2008). Therefore, diminished recruitment of cDC2s and/or reduced in situ DC differentiation (and therefore delayed or attenuated CD8+ T cell responses) may also contribute more severe disease in older patients.

At the time this study was conceived, DC3s were not yet identified. Guided by a canonical approach and limited by nasopharyngeal cell recovery, we were unable to capture the true heterogeneity of monocyte and DC subsets within the human airways in this study. From later reports establishing DC3 as a distinct DC subset arising from a specific progenitor (Bourdely et al., 2020; Cytlak et al., 2020; Dutertre et al., 2019), especially those describing dysregulated immune responses during SARS-CoV-2 infection (Winheim et al., 2021; Kvedaraite et al., 2021; Affandi et al., 2021), it appears that DC3 may be depleted during severe infection. As the pattern of overall DC depletion from circulation is shared between IAV and SARS-CoV-2 infections, it is plausible that DC3 may be present in the nasopharynx during acute IAV infection. As our comprehension of monocyte and DC heterogeneity expands, it is vital that studies like the present are carried out to accurately map the fate of newly discovered subsets in the airways.

During acute disease, monocytes present in/recruited to the nasopharynx likely contribute to sustained DC recruitment by secreting TNFα, CCL2, CCL3, and CCL7 locally (Oshansky et al., 2014; Gill et al., 2008; Marion et al., 2016). Due to the limited availability of cells in the NPA samples, demonstrating cytokine secretion from nasopharyngeal cells was not possible. However, we noted that in the nasopharynx, CMs, cDC2s, and cDC2s all appeared to mature by upregulating HLA-DR and/or CD86 expression as compared to cells in HCs, suggesting local activation, likely in response to the inflammatory milieu and/or virus exposure. CD86, a critical costimulatory molecule and ligand for CD28 and CTLA-4, is upregulated on monocytes and DCs upon virus infection in vitro and in vivo (Hubo et al., 2013). Lower expression of CD86 on circulating myeloid cells as compared to nasopharyngeal cells during IAV infection suggests migration of mature cells to the nasopharynx, and/or in situ differentiation of monocytes to induced DCs (that may not upregulate maturation markers) in blood during acute IAV infection as previously speculated (Cao et al., 2012). A non-human primate model of chronic simian immunodeficiency virus infection revealed sustained mobilization of MDCs from the bone marrow via blood to the intestinal mucosa, where MDCs remained activated and eventually underwent apoptosis (Wijewardana et al., 2013). In IAV infection, monocytes and DCs are likely recruited to the nasopharynx for a shorter period of time, where they face a similar fate. Some DCs likely traffic antigens to the lymph node to support adaptive responses (Cella et al., 1999; GeurtsvanKessel et al., 2008).

Nasopharyngeal CMs were also more mature in patients with higher viral RNA loads and their recruitment and/or differentiation may be aided by local cytokine production (TNFα and IL-6). Key innate inflammatory cytokines, including TNFα, IL-6, IFNα, IL-10, IL-15, and IL-18, were all significantly elevated early during infection (days 1–5) compared to HCs. TNFα levels strongly correlated with the presence of CMs in both blood and nasopharynx; despite the significant expansion of IMs in blood, supporting previous studies (Cole et al., 2017; Boyette et al., 2017; Dunning et al., 2018; Sprenger et al., 1996). We also demonstrated that the circulating CMs were the most frequent cellular source of TNFα among blood monocytes and DCs, while the TNFα at the site of infection may come from both CMs and the IMs (both subsets found in increased frequencies). Ex vivo, at steady state, human blood CMs and IMs have comparable TNFα secretion irrespective of the nature of stimulation (Boyette et al., 2017). IAV infection, therefore, may skew monocyte subset function, in addition to monocyte distribution and maturation. The broad range of TNFα, IL-6, and IFNα responses seen among the IAV patients suggest that seasonal IAV strains are associated with milder cytokine responses than those observed during infections with 2009 H1N1 pandemic influenza or highly pathogenic avian H5N1 strains (Oshansky et al., 2014; Sakabe et al., 2011; Dunning et al., 2018; Gerlach et al., 2013). Within the setting of seasonal influenza however, older patients had more IMs in the NPA and displayed stronger TNFα responses, locally and systemically.

During IAV infection, the significant expansion of CD14+CD16+ IMs in blood and the nasopharynx could be mediated by the presence of CCL2, a chemokine critical for monocyte chemotaxis (Dean et al., 2008). Upon CCL2 ligation, CCR2 facilitates CM and IM adhesion and transmigration from blood to tissues (Tsou et al., 2007). Therefore, in IAV patients, CCL2 may contribute to recruitment of monocytes and DCs from circulation to the nasopharynx to aid inflammation (Oshansky et al., 2014; Sprenger et al., 1996). Furthermore, elevated IFNα in circulation correlated with reduced viral RNA load, although we saw no evidence of this locally at the site of infection, suggesting that perhaps lower systemic IFN responses can indicate impaired control of viral replication in the nasopharynx, as previously reported (Dunning et al., 2018). This finding also supports previous studies showing that attenuated RIG-I signalling impairs IFN responses in the elderly (Molony et al., 2017) and very young (Marr et al., 2014), both groups at high risk of influenza-associated mortality.

During convalescence, monocyte and DC frequencies, and cytokine levels normalized in blood and the nasopharynx to levels seen in healthy individuals. The local and systemic inflammation observed, therefore, appears limited to the acute phase of disease and wanes during convalescence. Unlike patients infected with the pandemic 2009 H1N1 IAV strain during the pandemic years (2009–2010), where long-lasting immune perturbations were documented Lichtner et al., 2011; the repercussions of relatively mild seasonal IAV infections appear short-lived. This is also in contrast to in vivo studies which demonstrated prolonged DC activation and disruption of DC subset reconstitution in the lungs following IAV infection in mice (Strickland et al., 2014).

In April-May 2020, during the COVID-19 pandemic, the approach and methods described here allowed us to implement this study plan in a rapidly evolving pandemic. Although the patient cohorts were not identical, this endeavour proved the feasibility of using nasopharyngeal aspiration to assess local immune responses during respiratory viral infections. We observed that patients with IBV, RSV, or SARS-CoV-2 also displayed an influx of cells to the nasopharynx during infection. Despite annual reoccurrence of IBV and RSV infections, detailed investigations of the innate cells at the site of infection in patients are quite rare (Gill et al., 2008; Gill et al., 2005), and the technique we describe allows for minimally invasive longitudinal measurement of cellular and molecular aspects of infection. Patients with mild SARS-CoV-2 infection have not been studied as extensively as patients with severe or fatal COVID-19. The cell influx to the nasopharynx in COVID-19 patients did not appear to be due to monocytes but rather due to cDC2s and PDCs, which were reduced in blood, in line with previous reports (Zingaropoli et al., 2021; Peruzzi et al., 2020). Also in line with previous studies (Del Valle et al., 2020; Merad and Martin, 2020; Mudd et al., 2020), we found elevated levels of IL-6 in plasma, and also of TNFα. As different SARS-CoV-2 variants emerge, with concurrently increasing global vaccination rates, incomplete neutralization and/or protection and herd immunity may result in recurring mild SARS-CoV-2 infections. Understanding site-of-infection responses to mild SARS-CoV-2 infections is therefore increasingly relevant, and can be accomplished by the methods we describe in our study.

Finally, to further highlight the importance of studies like ours, we employed a high sensitivity, high-throughput proteomics platform to quantify differences in the nasopharyngeal proteome as compared to blood, in both IAV and SARS-CoV-2 infections. Additionally, this approach allows identification of proteins that cannot be identified by conventional assays that may be limited in breadth of proteome coverage or by limits of detection. We found differentially expressed proteins unique to blood or nasopharynx, and also to IAV or SARS-CoV-2. Preliminary pathway analysis reveals sizeable changes within the nasopharyngeal proteome during infection, especially during SARS-CoV-2 infection. In IAV patients, in line with previous reports (Marion et al., 2016) several innate immune pathway proteins were differentially enriched in the nasopharyngeal proteome, including TNF and IL-6, as seen from ELISA data.

The present study augments our current understanding of the role of monocyte and DC subsets during human respiratory viral infections by highlighting unique dynamics and location-specific functions for each subset over the course of infection. Acute human IAV infection is characterized by an expansion of IMs and monocyte-mediated cytokinemia driving monocyte and DC migration from blood to the nasopharynx, the initial site of IAV infection. Older patients with comorbidities display a recruitment pattern skewed towards IMs and increased TNF rather than CD1c+ MDCs which may contribute to more severe disease and longer duration of hospitalization observed in these patients. IBV, RSV, and mild SARS-CoV-2 infections elicit different patterns on immune cell recruitment to the nasopharynx as compared to IAV infections. We also illustrate the value of comparative high-resolution studies of immune cells in blood and at the site of infection, in order to fully understand their individual contributions to disease and how they orchestrate inflammation synergistically. Similar studies, carried out longitudinally across tissues, will aid resolution of these findings, and allow multivariate modeling of biomarkers of disease severity. Therapeutic approaches which allow selective modulation of monocyte and DC redistribution, maturation, and cytokine/chemokine function may hold the key to reducing influenza-associated disease burden and mortality in the future.

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Author details

1. Sindhu Vangeti

   Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Methodology, Writing – original draft, Project administration, Writing – review and editing

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0003-3404-6878

2. Sara Falck-Jones

   Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

3. Meng Yu

   Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

   Contribution

   Data curation, Formal analysis, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

4. Björn Österberg

   Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

   Contribution

   Data curation, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

5. Sang Liu

   Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

   Contribution

   Data curation, Investigation, Methodology, Writing – review and editing

   Competing interests

   No competing interests declared

6. Muhammad Asghar

   1. Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
   2. Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden

   Contribution

   Resources, Data curation, Supervision, Validation, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

7. Klara Sondén

   1. Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
   2. Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden

   Contribution

   Resources, Data curation, Supervision, Validation, Investigation, Writing – review and editing

   Competing interests

   No competing interests declared

8. Clare Paterson

   SomaLogic Operating Co., Inc,, Boulder, United States

   Contribution

   Data curation, Software, Formal analysis, Writing – review and editing

   Competing interests

   is an employee and stockholder of SomaLogic Inc

9. Penn Whitley

   Boulder Bioconsulting Inc, Boulder, United States

   Contribution

   Data curation, Software, Formal analysis, Writing – review and editing

   Competing interests

   is a consultant for Boulder Bioconsulting, Inc

10. Jan Albert

    1. Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden
    2. Department of Clinical Microbiology, Karolinska University Hospital, Stockholm, Sweden

    Contribution

    Resources, Data curation, Formal analysis, Supervision, Validation, Investigation, Methodology, Writing – review and editing

    Competing interests

    No competing interests declared

    "This ORCID iD identifies the author of this article:" 0000-0001-9020-0521

11. Niclas Johansson

    1. Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
    2. Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden

    Contribution

    Conceptualization, Resources, Data curation, Formal analysis, Supervision, Validation, Investigation, Methodology, Project administration, Writing – review and editing

    Competing interests

    No competing interests declared

12. Anna Färnert

    1. Division of Infectious Diseases, Department of Medicine Solna, Karolinska Institutet, Stockholm, Sweden
    2. Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden

    Contribution

    Conceptualization, Resources, Data curation, Validation, Investigation, Visualization, Methodology, Project administration, Writing – review and editing

    Competing interests

    No competing interests declared

13. Anna Smed-Sörensen

    Division of Immunology and Allergy, Department of Medicine Solna, Karolinska Institutet, Karolinska University Hospital, Stockholm, Sweden

    Contribution

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

    For correspondence

    anna.smed.sorensen@ki.se

    Competing interests

    is a consultant to Astra-Zeneca on studies not related to the present study

    "This ORCID iD identifies the author of this article:" 0000-0001-6966-7039

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