Interferon tone, timing, and mucosal inflammation as rival explanations for short-term heterologous interactions

Question: What mechanisms—interferon-mediated innate immunity, mucosal inflammation, and viral interference—have been proposed to explain short-term heterologous protection or enhanced susceptibility between respiratory viruses in cohort and challenge studies?

Answer

Taken together, the retrieved papers support a two-mechanism account in which direction of effect is set by which mechanism dominates. Protection is consistently attributed to a transient, epithelium-intrinsic interferon/ISG state — tonic or recently induced — that is narrow in its effector composition, decays over days to weeks, and is measurable as pre-exposure ISG tone; interference experiments show this state reduces the second virus's replication but is asymmetric and sequence-dependent, so it predicts viral load far better than it predicts disease. Enhanced susceptibility, by contrast, is almost never attributed to failed interferon in these papers: it is attributed to inflammation-driven changes in the target tissue (receptor upregulation on macrophages, mucus metaplasia and incomplete repair, IFN-γ-driven mucus and shedding, virus-induced loss of protective microbiota) and to cell-intrinsic superinfection exclusion kinetics that gate coinfection at the level of individual cells. Cohort data show both directions operating simultaneously and virus-specifically, with rhinovirus the most reproducible protector and SARS-CoV-2 and influenza the most reproducible short-term risk-increasing agents. The unresolved core is that interferon is treated in some papers as the causal effector and in others as an epiphenomenon of timing, and no retrieved study demonstrates a human heterologous challenge design that would discriminate between these.

Short-term protection tracks a transient epithelial interferon/ISG state, not adaptive immunity

Prior infection of differentiated primary bronchial epithelium confers protection against a subsequent, unrelated virus regardless of donor age or the identity of the first virus, and this cross-protection is driven by interferon signaling acting through a narrow, specific set of interferon-stimulated genes in both infected and bystander cells [2]. Within that set, IFI44L correlates most strongly with the level of cross-protection, and its overexpression alone is sufficient to reduce infection [2]. The protective interferon state need not be induced: depleting tonic type I/III interferons with neutralizing antibodies or scavengers in primary air-liquid-interface cultures reduced ISG expression and increased infectious rhinovirus production roughly 7–10 fold, while only HRV16 of the viruses tested elicited a strong early induced response [5]. Consistent with tone as the determinant, epithelium from exacerbation-prone asthmatic children shows lower pre-infection ISG expression and lower CXCL10 protein and supports greater rhinovirus replication, and prophylactic IFN-β normalizes the downstream response [11]. Age differences in this tone are proposed as a susceptibility mechanism: interferon epsilon is expressed at lower levels in nasal epithelium from newborns than from one-year-olds and induces a transient, temporally distinct ISG profile [4]. In naturally infected humans, type I interferon responses begin concurrently across nasal, oral and oropharyngeal sites even before local viral detection, whereas earlier nasal type II interferon initiation is associated with reduced local viral replication, prior vaccination and tissue-resident memory signatures [25].

Interference is asymmetric and sequence-dependent, so interferon induction predicts viral load but not disease

Influenza A virus reduced RSV replication by almost 3.0 logs when RSV was given at the peak of influenza-induced interferon, but the reciprocal effect was not observed [1]. Critically, the same study reports that interference depended on timing and sequence but not on differential interferon susceptibilities, and that influenza-infected mice challenged with RSV or with vehicle alone lost more weight and survived worse than singly infected mice, with similar interferon, cytokine and pulmonary inflammation between groups — disease worsening being attributed to aggravated pulmonary congestion after intranasal fluid instillation [1]. Effector mechanisms downstream of interferon diverge by type: type III interferon restricts influenza by promoting rapid death of infected epithelial cells rather than solely by JAK/STAT-driven ISG expression, with IFNLR1 knockout increasing the proportion of infected cells, while type I interferons given before infection suppress both influenza and RSV spread more effectively [8]. Interferon is also not sufficient to clear infection: in RSV-infected primary airway cultures only a subset of infected cells produced type I and III interferons, bystander cells showed strong ISG signatures, and neither interferon treatment nor ISG induction eliminated infection [3]. Whether a cell can mount the response at all is partly cell-intrinsic, since pre-infection expression of the ISG OASL is required for robust IFN-λ induction during influenza infection [10], and MAVS is non-redundantly required for type I and III interferon induction and for restricting influenza replication in primary human respiratory epithelium [9]. A cell-level mechanism independent of interferon also exists: SARS-CoV-2 superinfection exclusion begins within the first hour of primary infection and falls exponentially with delay, restricting coinfection to a narrow interface between spreading infections and thereby limiting genetic exchange [14].

Enhanced susceptibility is attributed to inflammatory and barrier remodeling rather than to interferon failure

Macrophage susceptibility to SARS-CoV-2 is increased by IL-1β-driven NF-κB transcription of ACE2, making inflammatory signaling itself a mechanism of heightened permissiveness [33]. Airway epithelium repairs after SARS-CoV-2 to an abnormal mucus-metaplastic, inflammatory state rather than to baseline, and repair is infection-severity-dependent and prolonged beyond 14 days in vitro [16]. In Down syndrome, RSV severity is attributed not to impaired viral control — trisomic cells actually show hyperactive interferon signaling and reduced RSV infectivity — but to heightened CXCL5/CXCL10 production and diminished type III interferon in vivo [6]. Pediatric nasal single-cell atlases show virus-specific mucosal programs rather than a single inflammatory axis: a robust interferon response in SARS-CoV-2, an IL-13-responsive secretory program in rhinovirus, and heightened inflammatory and cytotoxic activation in RSV, with interferon-response signatures and specific immune subsets associated with RSV severity [20]. Interferon-γ-driven mucosal inflammation (cytokines, immune recruitment, mucus hypersecretion) correlates with influenza shedding, and IFN-γ deficiency reduces mucus, shedding and transmission [19]. Mucus itself is a virus-selective barrier: penetration efficiency differs between viruses, and MUC5AC- or MUC5B-deficient epithelium yields higher influenza titers [23]. Virus-induced microbiota change is a further proposed mediator, with respiratory viruses increasing acquisition of Haemophilus influenzae, Moraxella catarrhalis and Streptococcus pneumoniae and depleting putatively beneficial taxa in 2,409 infant nasopharyngeal swabs [18], and viral infection driving sustained Pseudomonas expansion alongside IL-8 and IFN-λ1 in cystic fibrosis airways [17]. Bacterial colonization can in turn modify viral interference, since pneumococcal precolonization reduced RSV levels and blunted RSV-induced inflammatory and immune gene programs [15].

Trained innate and mucosal T-cell memory extend the protective window and can also cause harm

Prior RSV infection protected mice against subsequent SARS-CoV-2 in a dose- and time-dependent manner, with lung γδ T cell expansion and metabolic upregulation required, since TCRδ-deficient mice showed reduced SARS-CoV-2-reactive mucosal T cells and higher viral loads and inflammation [12]. Nasal CD4 tissue-resident memory T cells persist after influenza and provide heterosubtypic protection, with CXCR6–CXCL16 driving residency and Th17 cells aiding local clearance and limiting tissue damage [24]. Type I interferon acts as the priming signal for lasting transcriptional imprints in alveolar macrophages, conferring trained immunity that balances anti-bacterial and anti-tumour responses [31]. Trained immunity is not uniformly beneficial: β-glucan reprogramming of alveolar macrophages exacerbates lung injury after poly(I:C) challenge via a neutrophil/IFN-γ-dependent route [32]. Cross-reactive T cell immunity is also inducible: rhinovirus VP0 vaccination elicits airway CD4 and CD8 responses that expand on heterotypic challenge and accelerate clearance [22]. Antibody-based heterology is an alternative route to protection, as recent endemic coronavirus infection associates with higher cross-reactive Fc receptor-binding antibodies against SARS-CoV-2 S2 despite no difference in neutralizing antibodies or T cell responses [13].

Cohort data show protection and enhanced susceptibility coexisting, virus-specifically

In a prospective cohort of 3,560 participants with weekly nasal swabs, adjusted hazard ratios in the two weeks after an illness were predominantly below 1, and recent rhinovirus illness was associated with lower risk of endemic coronavirus, parainfluenza and RSV illness (aHRs 0.07–0.27), whereas SARS-CoV-2 illness was associated with higher short-term risk of adenovirus and parainfluenza illness (aHRs 3.20–3.33) and recent influenza in children aged 6 months to 4 years with higher short-term SARS-CoV-2 risk; including asymptomatic infections generally attenuated these associations [26]. Population-level modelling of post-2009-pandemic RSV activity identified three compatible interference mechanisms — reduced susceptibility to RSV coinfection, shortened RSV infectious period, or decreased RSV infectivity in co-infections [30]. Influenza vaccination was associated with reduced non-influenza respiratory virus infection in children (IRR 0.54 and 0.60 across two seasons), interpreted as support for virus interactions shaping infection dynamics [29]. Surveillance co-detection analysis found both positive and negative pairwise pathogen associations that varied by age group and study period [27], and one-third of severe lower respiratory illnesses in a birth cohort involved multiple viral species, with co-infection associated with 2.92-fold greater odds of severe versus upper respiratory illness [28].

Conflicts and gaps

The direction of the SARS-CoV-2 interaction is directly contested: cohort hazard ratios indicate increased short-term risk of adenovirus and parainfluenza after SARS-CoV-2 illness [26], while murine and epithelial work shows heterologous protection against SARS-CoV-2 after RSV [12] and interferon-mediated cross-protection between unrelated viruses [2]; whether the cohort signal is biological, behavioural, or an artefact of differential testing is not resolved by these papers. The causal status of interferon is unsettled: one study explicitly excludes differential interferon susceptibility as the basis of interference while attributing worsened disease to fluid instillation rather than inflammation [1], and RSV infection persists despite ISG induction [3]. Which interferon-driven effector matters is unresolved, with a narrow ISG set and IFI44L proposed for epithelial cross-protection [2], tonic type I/III interferon for baseline restriction [5], and type III-triggered cell death for influenza restriction [8]. Severity and susceptibility are conflated throughout: Down syndrome epithelium shows reduced infectivity alongside greater disease [6], and RSV severity associates with stronger, not weaker, interferon-response signatures [20]. No retrieved paper reports a human heterologous sequential challenge demonstrating the protective mechanism directly; the controlled influenza transmission trial described here produced no transmission at all, limiting inference [21].

What would change the answer

A staggered controlled human infection design — rhinovirus followed at defined intervals by SARS-CoV-2 or influenza, with daily paired nasal/oropharyngeal sampling and pre-challenge ISG tone measurement — would establish whether epithelial interferon tone mediates protection in humans and at what decay interval, building on the paired-site longitudinal design already used in natural infection [25]. Formal causal mediation of cohort hazard ratios by measured pre-exposure nasal ISG or IFI44L levels would test whether the observed virus-specific hazard ratios [26] are explained by interferon tone or by exposure behavior. CRISPR knockout of IFI44L, OASL and LY6E in primary air-liquid-interface epithelium subjected to sequential heterologous infection would identify which ISGs are necessary rather than merely correlated [2]. Because entry restriction is ISG-dependent and virus-specific, a knockout screen across respiratory cells would separate entry-level from replication-level interference [7]. Finally, time-resolved single-cell atlases of nasal mucosa sampled before and after heterologous exposure would distinguish inflammatory remodeling from antiviral protection as the substrate of enhanced susceptibility [20].

References

[1] Gilbert-Girard, S., Piret, J., Rheaume, C., Carbonneau, J., Goyette, N., Couture, C., Boivin, G.. "Influenza A Virus Interferes With Respiratory Syncytial Virus in Mice and Reconstituted Human Airway Epithelium". bioRxiv. 2025-02-19T00:00:00.000Z. URL: https://doi.org/10.1101/2025.02.19.639117

[2] Tymchenko, A., Fierville, M., Esteves, P., Gourdan, P., Germain, S., Ben-Sghaier, R., Faure, M., Roger, B., Rayne, F., Landrein, N., Magnone, V., BARBRY, P., Berger, P., Beaufils, F., Zaragosi, L.-E., Wodrich, H., Trian, T.. "A distinct signature of interferon-stimulated genes linked to cross-protection against secondary viral infections in primary bronchial epithelial cells". bioRxiv. 2026-07-01T00:00:00.000Z. URL: https://doi.org/10.64898/2026.06.30.735481

[3] Berg, K., Haid, S., Vafadarnejad, E., Carpentier, A., Geffers, R., Wiegmann, B., Saliba, A.-E., Erhard, F., Pietschmann, T.. "Respiratory syncytial virus load-dependent ciliated cell dedifferentiation and downregulation of immune response genes". bioRxiv. 2025-08-01T00:00:00.000Z. URL: https://doi.org/10.1101/2025.08.01.666372

[4] McCabe, M., Groves, H. E., Getty, E., Campbell, E., Bamford, C. G. G., Lopez Campos, G., Shields, M. D., Power, U. F.. "Age-dependent expression and antiviral activity of interferon epsilon in respiratory epithelium". bioRxiv. 2025-04-11T00:00:00.000Z. URL: https://doi.org/10.1101/2025.04.08.647778

[5] Sivarajan, R., Kirchgatterer, P. C., Lawrenz, J., Tanner-Matiz, E., Lindenmayer, J., Renz, V., Joshi, T., Oberwinkler, H., Walles, T., Fois, G., Kleger, A., Frick, M., Münch, J., Gaidt, M. M., Steinke, M., Sparrer, K. M.. "Tonic interferons defend against respiratory viruses in primary human lung organoid-derived air-liquid interface cultures". bioRxiv. 2025-12-11T00:00:00.000Z. URL: https://doi.org/10.64898/2025.12.10.693424

[6] Chorvinsky, E., Bhattacharya, S., Bera, B. S., Welham, A. L., Hussain Ismat, K., Lawlor, C. M., Preciado, D., Gomez Villalobos, J., Morizono, H., Pillai, D., Gutierrez, M. J., Jaiswal, J., Nino, G.. "Dysregulated airway epithelial antiviral immunity in Down Syndrome impairs type III IFN response and amplifies airway inflammation during RSV infection.". bioRxiv. 2024-11-25T00:00:00.000Z. URL: https://doi.org/10.1101/2024.11.22.624921

[7] Stoddard, C. I., Litchford, M. L., Sung, K., Hutcheson, R. L., Marceau, J., Johnson, T., Ota, A., Baumgarten, N. E., Gale, M., Overbaugh, J.. "A knockout screening platform for interferon-stimulated genes in respiratory cells identifies LY6E as a dominant antiviral effector against coronaviruses". bioRxiv. 2026-09-23T00:00:00.000Z. URL: https://doi.org/10.64898/2026.09.21.751853

[8] Prus, W., Grabowski, F., Koza, P., Korwek, Z., Czerkies, M., Kaczynska, P., Amirinejad, N., Kochanczyk, M., Lipniacki, T.. "Type III interferons may suppress viral infections by triggering cell death". bioRxiv. 2025-09-17T00:00:00.000Z. URL: https://doi.org/10.1101/2024.09.09.612051

[9] Hemberg, M., Hansen, A. L., Storgaard, J., Blay-Cadanet, J., Pedersen, A., Thielke, A. L., Holm, C. K.. "MAVS is Important for Antiviral Defense Against InfluenzaA Virus in a Human Respiratory Epithelium Model". bioRxiv. 2025-12-11T00:00:00.000Z. URL: https://doi.org/10.64898/2025.12.09.693221

[10] Rivera-Cardona, J., Mahajan, T., Kakuturu, N. R., Teo, Q. W., Lederer, J., Thayer, E. A., Rowland, E. F., Heimburger, K., Sun, J., McDonald, C. A., Mickelson, C. K., Langlois, R. A., Wu, N. C., Milenkovic, O., Maslov, S., Brooke, C. B.. "Intrinsic OASL expression licenses interferon induction during influenza A virus infection". bioRxiv. 2025-03-17T00:00:00.000Z. URL: https://doi.org/10.1101/2025.03.14.643375

[11] Jayavelu, N. D., Benson, B., dela Cruz, P. C., Powell, W. T., Rich, L. M., Vanderwall, E. R., Gates, C. R., Nagel, A. J., White, M. P., Samanas, N. B., Whitfield, K., Hallstrand, T. S., Ziegler, S. F., Debley, J. S.. "Transcriptomic Profiling of Bronchial Epithelium Reveals Dysregulated Interferon and Inflammatory Responses to Rhinovirus in Exacerbation-Prone Pediatric Asthma". bioRxiv. 2025-10-19T00:00:00.000Z. URL: https://doi.org/10.1101/2025.10.19.683298

[12] Adam, A., Wu, W., Jones, M. C., Hao, H., FNU, A., Samir, P., Bao, X., Wang, T.. "Respiratory syncytial virus infection confers heterologous protection against SARS-CoV-2 via induction of γδ T cell-mediated trained immunity and SARS-CoV-2 reactive mucosal T cells". bioRxiv. 2025-07-07T00:00:00.000Z. URL: https://doi.org/10.1101/2025.07.02.662833

[13] Bean, D. J., Liang, Y. M., Sagar, M.. "Recent Endemic Coronavirus Infection Associates With Higher SARS-CoV-2 Cross-Reactive Fc Receptor Binding Antibodies". bioRxiv. 2024-10-23T00:00:00.000Z. URL: https://doi.org/10.1101/2024.10.23.619886

[14] Sims, A., Weir, D., Cole, S. J., Hutchinson, E.. "SARS-CoV-2 cellular coinfection is limited by superinfection exclusion.". bioRxiv. 2025-01-27T00:00:00.000Z. URL: https://doi.org/10.1101/2025.01.26.634807

[15] Kafer, L. A., F. Escapa, I., Boyd, A. I., Rivera Tostado, A., Kambal, A., Blutt, S., Avadhanula, V., Piedra, P. A., Lemon, K. P.. "Streptococcus pneumoniae colonization modulates human nasal epithelial responses to respiratory syncytial virus infection". bioRxiv. 2026-02-05T00:00:00.000Z. URL: https://doi.org/10.64898/2026.02.05.703985

[16] Dang, H., Edwards, C. E., Kato, T., Reidel, B., Meganck, R. M., Esther, C. R., Ehre, C., Fulcher, M. L., Bailey, A. B., Cooley, M. R., Mikami, Y., Asakura, T., Hawkins, P. E., Saito, M., Meyers, J. L., Konopka, K., Gerayeli, F. V., Park, H. Y., Sin, D. D., Livraghi-Butrico, A., Okuda, K., Pickles, R. J., Klein, S. L., Randell, S. H., O'Neal, W. K., Baric, R. S., Boucher, R. C.. "Airway Epithelial SARS-CoV-2 Infectious and Repair Responses: Relationships to Age, Sex, and Post-COVID Pulmonary Syndromes". bioRxiv. 2025-09-02T00:00:00.000Z. URL: https://doi.org/10.1101/2025.07.17.663733

[17] Hilliam, Y., Armbruster, C. R., Atteih, S. E., Rapsinski, G. J., Moore, J., Koirala, J., Krainz, L., Gaston, J. R., Williams, J., Cooper, V. S., Lee, S. E., Bomberger, J. M.. "Respiratory viral infection is associated with increased Pseudomonas abundance in cystic fibrosis airways". bioRxiv. 2025-07-08T00:00:00.000Z. URL: https://doi.org/10.1101/2025.07.08.663034

[18] Kelly, M. S., Shi, P., Boiditswe, S. C., Qin, E., Steenhoff, A. P., Mazhani, T., Patel, M. Z., Cunningham, C. K., Rawls, J. F., Luinstra, K., Gilchrist, J., Maciejewski, J., Hurst, J. H., Seed, P. C., Bulir, D., Smieja, M.. "The role of the microbiota in respiratory virus-bacterial pathobiont relationships in the upper respiratory tract". medRxiv. 2024-10-23T00:00:00.000Z. URL: https://doi.org/10.1101/2024.10.22.24315478

[19] Bartlett, S., Rocha, H. L., Hsieh, L. L., Yeung, S. T., Wang, C., Ciabattoni, G. O., Loomis, C. A., Li, H., tenOever, B., Ortigoza, M. B.. "IFNγ-Driven Inflammatory Responses in the Nasal Mucosa Drive Influenza Virus Shedding and Transmission". bioRxiv. 2026-01-07T00:00:00.000Z. URL: https://doi.org/10.64898/2026.01.06.698034

[20] Walsh, J. M. L., Juttukonda, L. J., Tang, Y., Chatterjee, A., Elosua-Bayes, M., Langan, E., Frischmann, A., Taliaferro, F., Matthews, H. R., Kimler, K., Lent, C. M., Purna Keya, D., Chondrow Dev, P., Rajib Malaker, A., Tanvia, L., Mohammad Tanmoy, A., Ghosh, S., Maitra, A., Ghosh, A., Basu, S., Kane, A. S., Coomer, C. A., Shalek, A. K., de Silva, T. I., Sesay, A. K., Edwards, J., Sin Quee, C., Gonzalez, W. I., Yonker, L. M., Glover, S. C., Majumder, P., Hooda, Y., Saha, S., Ordovas-Montanes, J., Horwitz, B. H.. "Unique nasal cell states induced by common pediatric respiratory viruses". bioRxiv. 2026-04-24T00:00:00.000Z. URL: https://doi.org/10.64898/2026.04.20.719671

[21] Lai, J., Sobhani, H., Coleman, K. K., Tai, S.- H. S., Hong, F., Sierra Maldonado, I., Esparza, Y., McPhaul, K. M., Zhu, S., DeVoe, D. L., Ortiz, J. R., Chen, S., Yellin, T., Carreno, J. M., Krammer, F., Cowling, B. J., Gordon, A., Chen, W. H., Srebric, J., Milton, D. K.. "Evaluating Modes of Influenza Transmission (EMIT-2): Insights from a Controlled Human Influenza Virus Infection Transmission Trial (CHIVITT)". medRxiv. 2025-12-02T00:00:00.000Z. URL: https://doi.org/10.1101/2025.04.28.25326458

[22] Shaw, S. M., Pyle, C. J., Patel, N. D., Edwards, M. R., Wang, Z., Tregoning, J., Londono-Hayes, P., Hamblin, P. A., Butt, R. P., Johnston, S. L.. "A rhinovirus vaccine evokes T cell mediated cross-reactive immunity in a preclinical model of rhinovirus infection". bioRxiv. 2026-01-07T00:00:00.000Z. URL: https://doi.org/10.64898/2026.01.06.697896

[23] Corkran, M., Engle, E. M., Pan, H., Kumar, S., Boboltz, A., Johnson, J. R., Duncan, G. A., Scull, M. A.. "An Inverse Transwell Assay for Airway Mucus Barrier Function Reveals both Virus- and Mucin-Specific Impacts on Infection". bioRxiv. 2026-07-19T00:00:00.000Z. URL: https://doi.org/10.64898/2026.07.19.739437

[24] Mathew, N. R., Gailleton, R., Scharf, L., Schön, K., Enriquez, J., Axelsson, H., Strömberg, A., Lycke, N., Bemark, M., Tang, K.-W., Angeletti, D.. "Nasal tissue-resident memory CD4+ T cells persist after influenza A virus infection and provide heterosubtypic protection". bioRxiv. 2025-09-25T00:00:00.000Z. URL: https://doi.org/10.1101/2024.07.06.602325

[25] Winnett, A. V., Tabachnikova, A., Chen, J., Greene, K., Romano, A. E., Pei, X. P., Cooper, M. M., Silva, J., Carter, A. M., Jiang, J., Kong, Y., Roos, M., Middle, C., Zhang, H., Thomson, M., Booher, K., Kuersten, S., Iwasaki, A., Ismagilov, R. F.. "Early Mucosal Type II Interferon Limits SARS-CoV-2 Replication in Humans". medRxiv. 2026-07-01T00:00:00.000Z. URL: https://doi.org/10.64898/2026.06.29.26356894

[26] Hoffman, K. L., Weil, A. A., Wetzler, E. A., Akinola, B. O., Beauge, A., Andy, C., Adams, A., Frivold, C., Cox, S. N., Ehmen, B., Hatchie, T., Clark, E. L., Drummond, M., Englund, J., Han, P. D., Kuntz, J. L., Lo, N. C., Lockwood, C., Starita, L., Mularski, R. A., Naleway, A. L., Carone, M., Chu, H. Y.. "Interactions between respiratory viruses in US adults and children: a prospective cohort study". medRxiv. 2026-10-19T00:00:00.000Z. URL: https://doi.org/10.64898/2026.10.15.26365672

[27] Takeuchi, J. S., Kurokawa, M., Yamamoto, K., Yamanaka, J., Morino, E., Takayanagi-Nishisako, S., Ohmagari, N., Sugiura, W., Kimura, M.. "Post-pandemic ecological reshaping of respiratory pathogen circulation: A six-year FilmArray(R)-based surveillance study in Tokyo, Japan (2020-2026)". medRxiv. 2026-09-02T00:00:00.000Z. URL: https://doi.org/10.64898/2026.08.28.26360747

[28] Moore, C. M., Secor, E. A., Fairbanks-Mahnke, A., Everman, J. L., Elhawary, J. R., Witonsky, J. I., Pruesse, E., Chang, C.-H., Contreras, M. G., Eng, C., Canales, K., Rosado, T., Hu, D., Huntsman, S., Jackson, N. D., Li, Y., Lopez, N., Valentin, A. M., Medina, V., Montanez-Lopez, C. A., Morin, A., Nieves, N. A., Oh, S. S., Otero, R. A., Colon, R., Rodriguez, L., Sajuthi, S. P., Salazar, S., Serrano, G., Morales, E. V., Vazquez, G., Morales, N. V., Williams, B. J. M., Zhang, P., Sheppard, D., Santana, J. R. R., Seibold, M. A.. "Independent and interactive effects of viral species on risk for lower respiratory tract illnesses in early life". medRxiv. 2025-02-26T00:00:00.000Z. URL: https://doi.org/10.1101/2025.02.25.25322678

[29] Giorcelli, A., Rigamonti, V., Rocchi, M., Ieva, F., Torri, V., Cavinato, L., Morris, S. K., Cotugno, N., Palma, P., Nordeng, H., Trinh, N. T., Dona', D., Giaquinto, C., Di Chiara, C., Cantarutti, A.. "Dynamics of Influenza Vaccination and Respiratory Virus Infections in Children: A Multistate Model Approach". medRxiv. 2026-01-11T00:00:00.000Z. URL: https://doi.org/10.64898/2026.01.08.26343664

[30] Li, K., Thindwa, D., Weinberger, D. M., Pitzer, V. E.. "The role of viral interference in shaping RSV epidemics following the 2009 H1N1 influenza pandemic". medRxiv. 2025-02-19T00:00:00.000Z. URL: https://doi.org/10.1101/2024.02.25.24303336

[31] Wang, T., Zhang, J., Miao, Y., Wang, Y., Li, Y., Wang, L., Liu, Y., Chang, C.-W., Chen, E., Yao, Y.. "Type-I interferon priming signal balances anti-bacterial and anti-tumor trained immunity in alveolar macrophages". bioRxiv. 2025-06-17T00:00:00.000Z. URL: https://doi.org/10.1101/2025.06.14.659659

[32] Prevel, R., Pernet, E., Tran, K. A., Sadek, A., Sadeghi, M., Lapshina, E., Jurado, L., Kristof, A. S., Moumni, M., Poschmann, J., Divangahi, M.. "β-glucan reprograms alveolar macrophages via neutrophil/IFNγ axis to promote lung injury". bioRxiv. 2025-01-27T00:00:00.000Z. URL: https://doi.org/10.1101/2024.09.02.610842

[33] Lee, C., Khan, R., Mantsounga, C. S., Sharma, S., Pierce, J., Amelotte, E., Butler, C. A., Farinha, A., Parry, C., Caballero, O., Morrison, J. A., Uppuluri, S., Whyte, J. J., Kennedy, J. L., Zhang, X., Choudhary, G., Olson, R. M., Morrison, A. R.. "IL-1β-driven NF-κB transcription of ACE2 as a Mechanism of Macrophage Infection by SARS-CoV-2". bioRxiv. 2025-02-13T00:00:00.000Z. URL: https://doi.org/10.1101/2024.12.24.630260

How this survey was made

This survey answers one question: “What mechanisms—such as interferon-mediated innate immunity, mucosal inflammation, and viral interference—have been proposed to explain short-term heterologous protection or enhanced susceptibility between respiratory viruses in cohort and challenge studies?”

We keep our own collection of recent preprints and refresh it every day from bioRxiv, medRxiv, arXiv, PsyArXiv, SocArXiv and ChemRxiv. For each survey, we search that collection for recent work and keep the strongest matches: papers that use the same terms as the question, and papers on the same topic in different words.

The text was written from the titles and abstracts of those papers; the full texts were not read. Statements that draw on a particular paper are marked with a number in brackets. The reference list just above is the 33 papers whose work this text draws on, chosen from the 118 papers those searches returned; the rest of the shortlist is not printed. It is not a complete review of everything published on the question.

Treat this as a starting point and a reading list, not a peer-reviewed review. The searches behind this survey ran on October 22, 2026 and covered work from the previous two years.