Baseline T cell immune phenotypes predict virologic and disease control upon SARS-CoV infection in Collaborative Cross mice

Abstract

The COVID-19 pandemic has revealed that infection with SARS-CoV-2 can result in a wide range of clinical outcomes in humans. An incomplete understanding of immune correlates of protection represents a major barrier to the design of vaccines and therapeutic approaches to prevent infection or limit disease. This deficit is largely due to the lack of prospectively collected, pre-infection samples from indiviuals that go on to become infected with SARS-CoV-2. Here, we utilized data from genetically diverse Collaborative Cross (CC) mice infected with SARS-CoV to determine whether baseline T cell signatures are associated with a lack of viral control and severe disease upon infection. SARS-CoV infection of CC mice results in a variety of viral load trajectories and disease outcomes. Overall, a dysregulated, pro-inflammatory signature of circulating T cells at baseline was associated with severe disease upon infection. Our study serves as proof of concept that circulating T cell signatures at baseline can predict clinical and virologic outcomes upon SARS-CoV infection. Identification of basal immune predictors in humans could allow for identification of individuals at highest risk of severe clinical and virologic outcomes upon infection, who may thus most benefit from available clinical interventions to restrict infection and disease.

Distinct gene programs underpinning 'disease tolerance' and 'resistance' in influenza virus infection

“…It has been long argued whether death resulting from dysregulation of inflammation in sepsis is due to a poor initial immune response followed by high pathogen burden and secondary hyper-inflammation or, alternatively, is due to a disproportionately strong initial immune response against a low pathogen burden that leads to inadequate systemic responses. Our findings argue for the former, in line with studies of bacterial sepsis 41 and respiratory infections [42][43][44] , and consistent with the efficacy of approaches that boost the baseline/early resistance such as vaccines 45,46 .…”

Novel Mouse Model of Murine Cytomegalovirus–Induced Adaptive NK Cells

“…Such interrogation may provide insights into the development of adaptive NK cells in humans with a much broader range of genetic variability, relative to inbred mice. These investigations should incorporate numeric assessment of NK cells across tissues and may be further extended through the breeding of F 1 mice with either strains of interest or some of the classical inbred strains, as has been previously investigated (25). These analyses may elucidate the molecular underpinnings for variation in the baseline differences in NK cell number and expression of NK cell receptors such as Ly49H.…”

A regulatory T cell signature distinguishes the immune landscape of COVID-19 patients from those with other respiratory infections

“…Thus, additional studies are required to determine whether T reg -modulating therapies could be of benefit in limiting COVID-19 severity. We recently demonstrated that in a mouse model of SARS-CoV, an elevated steady-state, preinfection frequency of T regs correlates with protection from high viral loads and disease upon infection ( 70 ), thereby contributing to the notion that T regs could play a protective role in limiting disease. However, examination of prospectively collected pre–COVID-19 pandemic samples from humans that went on to become infected would be required to establish whether T reg abundance is predictive of viral loads or disease severity upon SARS-CoV-2 infection.…”