Core body temperature increases host resistance to influenza virus and SARS-CoV-2 infection

A recent article on the research place* The preprint server showed that high body temperature increases gut microbiota-dependent host resistance to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and influenza A virus infection.

To learn: High body temperature increases gut microbiota-dependent host resistance to influenza A virus and SARS-CoV-2 infections. Photo credit: iunewind/Shutterstock

background

Respiratory diseases such as influenza and coronavirus disease 2019 (COVID-19) cause significant mortality and morbidity, mostly affecting the elderly. Fever is a common feature of COVID-19 and influenza, although its physiological importance in host resistance to viral infections is unclear. The relevance of additional age-related changes in host variables other than impaired signaling of type I interferons (IFNs) to susceptibility to influenza virus infection is unknown.

Several studies have shown that the composition of the gut microbiota varies with age in both animals and humans. In addition, the average body temperature decreases with age. Although there is increasing evidence that the gut microbiota and its metabolites are critical in protecting against influenza infection, the impact of core body temperature on host defenses against influenza virus infection remains largely uncertain.

The authors of the current study previously noted that mice exposed to a high ambient temperature of 36°C showed impaired virus-selective CD8+ T-cell responses and antibody production after intranasal treatment with a sublethal dose of 30 pfu of the influenza virus. However, the influence of outside temperature on the host’s resistance to a deadly influenza virus remains unknown.

About the study

In the present study, the scientists examined the influence of body core and external temperature on the host’s resistance to influenza infections. They tested the host’s resistance to SARS-CoV-2 or influenza virus infection by exposing mice to a high ambient temperature of 36 °C.

Mice were maintained at 36, 22, or 4°C for one week prior to infection with influenza virus. Mice exposed to high heat, cold, and room temperature (RT) were infected intranasally with a mouse-adapted influenza A virus strain A/Puerto Rico/8/1934 (PR8) and maintained at 36, 22, or 4°C during throughout the duration of the assessments to examine the effect of core body temperature on protection against influenza virus infection.

The authors caged mice at 36, 34, 28, or 22 °C before infecting them with the influenza virus to establish the minimum core body temperature needed to protect against infection. They infected antibiotic (Abx)-treated or low-fiber (LF)-fed mice exposed to high heat to see if microbial metabolites or gut microbiota were required to improve the host’s resistance to influenza virus infection.

Researchers performed gas chromatography-mass spectrometry (GC-MS), capillary electrophoresis-time-of-flight-mass spectrometry (CE-TOFMS), and liquid chromatography-tandem mass spectrometry (LC-MS/MS) targeting metabolome-centric metabolome assessment of serum, cecal contents, and livers of naïve mice maintained at 36, 22, or 4 °C for one week to assess the mechanisms underlying gut microbiota-derived metabolites inducing host resistance to influenza infection in severely heat-exposed mice.

In addition, the team examined the inhibitory effect of bile acids on SARS-CoV-2 infection. In the absence or presence of bile acids, they infected VeroE6/TMPRSS2 cells with SARS-CoV-2. In addition, the scientists examined the relationship between plasma bile acid titers in COVID-19 patients and the severity of the disease.

Results

The study results show that exposure of mice to a high ambient temperature of 36 °C increases host resistance to viral pathogens such as influenza and SARS-CoV-2. Mice exposed to high heat raise their basal body temperature to over 38 °C, allowing more bile acid to be produced in gut and serum in a gut microbiota-dependent manner.

High body temperature increases the resistance of gut microbiota-dependent host cells to influenza virus infection.  Mice were maintained at 22, 28, 34, or 36°C for 7 days prior to influenza virus infection and throughout infection.  a, The body temperature of naïve mice maintained at 22, 28, 34 or 36 °C was measured.  bd, Mice maintained at 22, 28, 34, or 36°C were infected intranasally with 1,000 pfu of influenza virus.  Mortality (b), core body temperatures (c), and viral titers in the lung wash (d) were measured on the indicated days after challenge.  e,f, LF-fed, Abx-treated and control mice maintained at 36°C were infected intranasally with 1,000 pfu of influenza virus.  Mortality (e) and core body temperatures (f) were measured on the indicated days after challenge.High body temperature increases the resistance of gut microbiota-dependent host cells to influenza virus infection. Mice were maintained at 22, 28, 34, or 36°C for 7 days prior to influenza virus infection and throughout infection. a, The body temperature of naïve mice maintained at 22, 28, 34 or 36 °C was measured. bd, Mice maintained at 22, 28, 34, or 36°C were infected intranasally with 1,000 pfu of influenza virus. mortality (b), body core temperatures (c) and virus titer in the lung lavage (i.e) were measured on the indicated days after the challenge. e, f, LF-fed, Abx-treated, and control mice maintained at 36°C were infected intranasally with 1,000 pfu of influenza virus. mortality (e) and body core temperatures (f) were measured on the indicated days after the challenge.

By limiting viral replication and neutrophilic tissue damage, expression of gut microbiota-derived deoxycholic acid (DCA) and its plasma membrane-bound receptor Takeda G protein-coupled receptor 5 (TGR5) increases host resistance to influenza virus infection.

Furthermore, the Syrian hamster was protected from severe SARS-CoV-2 infection by the DCA plus its farnesoid X nuclear receptor (FXR) agonist. In addition, the plasma of SARS-CoV-2 infected individuals with moderate 1 or 2 disease had lower levels of specific bile acids compared to the mild disease group.

Overall, the current results demonstrate an unexpected pathway by which resistance to SARS-CoV-2 and influenza viruses was increased in hosts in a gut microbiota-dependent manner via virus-induced high fever.

Conclusions

The study results revealed a previously unknown relationship between host resistance to viral infections, the effect of gut microbes and core body temperature. Researchers discovered that exposing mice to a high ambient temperature of 36 °C increased body temperature and increased host resistance to SARS-CoV-2 or influenza virus infections. In addition, the study found that activation of gut microbiota due to high body temperature increases gut and serum bile acid concentrations, which reduces viral replication and harmful inflammatory responses after SARS-CoV-2 and influenza virus infection.

In particular, the current article contributes to the understanding of how host resistance to SARS-CoV-2 and influenza infections was increased by core body temperature. The present conclusion that specific plasma bile acids were reduced in subjects with moderate 1/2 COVID-19 may illustrate the diversity of clinical disease manifestations in humans and support strategies to mitigate COVID-19 outcomes.

*Important NOTE

Preprints with Research Square Publish preliminary scientific reports that have not been peer-reviewed and therefore should not be taken as conclusive, guide clinical practice/health behaviors or be treated as established information.

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