High body temperature increases gut microbiota-dependent host resistance to influenza A virus and SARS-CoV-2 infection (preprint)

While a common symptom of influenza and coronavirus disease 2019 (COVID-19) is fever, its physiological role on host resistance to viral infection remains less clear. Here, we demonstrate that exposure of mice to the high ambient temperature of 36 °C increase host resistance to viral pathogens including influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High heat-exposed mice increase basal body temperature over 38 °C to enable more bile acids production in a gut microbiota-dependent manner. The gut microbiota-derived deoxycholic acid (DCA) and its plasma membrane-bound receptor Takeda G-protein-coupled receptor 5 (TGR5) signaling increase host resistance to influenza virus infection by suppressing virus replication and neutrophil-dependent tissue damage. Furthermore, the DCA and its nuclear farnesoid X receptor (FXR) agonist protect Syrian hamster from lethal SARS-CoV-2 infection. Moreover, we demonstrate that certain bile acids are reduced in the plasma of COVID-19 patients who developed moderate I/II disease compared with minor illness group. These findings uncover an unexpected mechanism by which virus-induced high fever increases host resistance to influenza virus and SARS-CoV-2 in a gut microbiota-dependent manner.

High body temperature increases microbiota-dependent host resistance to influenza A virus and SARS-CoV-2 infection (preprint)

While a common symptom of influenza and coronavirus disease 2019 (COVID-19) is fever, its physiological role on host resistance to viral infection remains less clear. Here, we demonstrate that exposure of mice to the high ambient temperature of 36 °C increase host resistance to viral pathogens including influenza virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). High heat-exposed mice increase basal body temperature over 38 °C to enable more bile acids production in a gut microbiota-dependent manner. The microbiota-derived deoxycholic acid (DCA) and its plasma membrane-bound receptor Takeda G-protein-coupled receptor 5 (TGR5) signaling increase host resistance to influenza virus infection by suppressing virus replication and neutrophil-dependent tissue damage. Furthermore, the DCA and its nuclear farnesoid X receptor (FXR) agonist protect Syrian hamster from lethal SARS-CoV-2 infection. Moreover, we demonstrate that certain bile acids are reduced in the plasma of COVID-19 patients who developed moderate I/II disease compared with minor illness group. These findings uncover an unexpected mechanism by which virus-induced high fever increases host resistance to influenza virus and SARS-CoV-2 in a microbiota-dependent manner.

Disruption of nasal bacteria enhances protective immune responses to influenza A virus and SARS-CoV-2 infection in mice (preprint)

Gut microbiota plays a critical role in the induction of adaptive immune responses to influenza virus infection. However, the role of nasal bacteria in the induction of the virus-specific adaptive immunity is less clear. Here we demonstrate that while intranasal administration of influenza virus hemagglutinin vaccine alone was insufficient to induce the vaccine-specific antibody responses, disruption of nasal bacteria by lysozyme or addition of culturable oral bacteria from a healthy human volunteer rescued inability of the nasal bacteria to generate antibody responses to intranasally administered the split-virus vaccine. Myd88-depdnent signaling in the hematopoietic compartment was required for adjuvant activity of intranasally administered oral bacteria. In addition, we found that the oral bacteria-combined intranasal vaccine induced protective antibody response to influenza virus and SARS-CoV-2 infection. Our findings here have identified a previously unappreciated role for nasal bacteria in the induction of the virus-specific adaptive immune responses.

Disruption of Nasal Bacteria Enhances Protective Immune Responses to Influenza A Virus and SARS-CoV-2 Infection (preprint)

Background: Gut microbiota and these microbial-derived products play a critical role in the induction of adaptive immune responses to influenza virus infection. However, the role of nasal bacteria in the induction of the virus-specific adaptive immunity is less clear. Here, we examine whether nasal bacteria critically regulates the generation of influenza virus specific adaptive immune response after infection or intranasal vaccination. Results: We demonstrated that disruption of nasal bacteria by topical mucosal application of antibiotic enhances the virus-specific antibody responses to influenza virus infection. Although intranasal administration of hemagglutinin (HA) vaccine alone was insufficient to induce the HA-specific antibody responses, disruption of nasal bacteria by lysozyme or addition of culturable oral bacteria from a healthy human volunteer rescued inability of the nasal bacteria to generate antibody responses to intranasally administered split-virus vaccines. Myd88-depdnent signaling in the hematopoietic compartment was required for adjuvant activity of intranasally administered oral bacteria. In addition, we found that the oral bacteria-combined intranasal vaccine induced protective antibody response to influenza virus and SARS-CoV-2 infection.Conclusion: We show for the first time that disruption of nasal bacteria enhances protective immune responses to influenza virus and SARS-CoV-2 infection. Our findings here have identified a previously unappreciated role for nasal bacteria in the induction of the virus-specific adaptive immune responses.