Immune predictors of mortality following RNA virus infection

Abstract

Background Virus infections result in a range of clinical outcomes for the host, from asymptomatic to severe or even lethal disease. Despite global efforts to prevent and treat virus infections to limit morbidity and mortality, the continued emergence and re-emergence of new outbreaks as well as common infections such as influenza persist as a health threat. Challenges to the prevention of severe disease after virus infection include both a paucity of protective vaccines, as well as the early identification of individuals with the highest risk that may require supportive treatment. Methods We completed a screen of mice from the Collaborative Cross (CC) that we infected with influenza, SARS-coronavirus, and West Nile virus. Results CC mice exhibited a range of disease manifestations upon infections, and we used this natural variation to identify strains with mortality following infection and strains exhibiting no mortality. We then used comprehensive pre-infection immunophenotyping to identify global baseline immune correlates of protection from mortality to virus infection. Conclusions These data suggest that immune phenotypes might be leveraged to identify humans at highest risk of adverse clinical outcomes upon infection, who may most benefit from intensive clinical interventions, in addition to providing insight for rational vaccine design.

Baseline T cell immune phenotypes predict virologic and disease control upon SARS-CoV infection

“…CC mice were obtained from the Systems Genetics Core Facility at the University of North Carolina-Chapel Hill (UNC) ( Welsh et al, 2012 ). As reported previously ( Graham et al, 2020 ), between 2012 and 2017, F1 hybrid mice derived from intercrossing CC strains (CC-RIX) were generated for this research study at UNC in an SPF facility based on the following principles: (1) Each CC strain used in an F1 cross had to have been certified distributable ( Welsh et al, 2012 ); (2) The UNC Systems Genetics Core Facility was able to provide sufficient breeding animals for our program to generate N=100 CC-RIX animals in a target three month window; (3) Each CC-RIX had to have one parent with an H2B b haplotype (from either the C57BL/6J or 129S1/SvImJ founder strains), and one parent with a haplotype from the other six CC founder strains; (4) Each CC had to be used at least once (preferably twice) as a dam, and once (preferably twice) as a sire in the relevant CC-RIX; (5) Lastly, we included two CC-RIX multiple times across the five years of this program to specifically assess and control for batch and seasonal effects. The use of CC-RIX allowed us to explore more lines than the more limited number of available RI strains, and additionally, CC-RIX lines were bred to ensure that lines were heterozygous at the H-2b locus, having one copy of the H-2b haplotype and one copy of the other various haplotypes.…”

“…Finally, in both our previous study as well as this focused study of SARS-CoV, we found that a restricted pro-inflammatory potential of T cells is correlated with protection from mortality upon infection with each of the three viruses ( Graham et al, 2020 ) as well as severe virologic outcomes upon SARS-CoV infection ( Figures 3 – 5 ). Specifically, we demonstrate that pre-infection ability of T cells to express the pro-inflammatory cytokine TNF correlated with more severe virologic outcomes ( Figures 3E – G ), as has been demonstrated as well for SARS-CoV and COVID-19 ( Blanco-Melo et al, 2020 ; Lucas et al, 2020 ; McDermott et al, 2016 ; Qin et al, 2020 ).…”

“…It stands to reason that such an active innate-like T cell response would need to be subject to immunoregulation in order to limit activity and prevent excess collateral damage. Also in our previous study, we found that an increased frequency of Tregs correlated with protection from death following each of the three infections (influenza A virus, West Nile virus, and SARS-CoV) ( Graham et al, 2020 ). Our results presented herein further support that an increased basal frequency of Tregs in the circulation correlates with protection both from early SARS-CoV viral replication, as well as from disease upon infection ( Figures 2 and 4 ).…”

“…In our previous study, we used data from our screen of CC mice to identify more universal immune correlates of mortality following infection with influenza, SARS-CoV, and WNV ( Graham et al, 2020 ). The protective signature included an increased level of basal T-cell activation that was associated with protection, which we also found here to be associated with protection from severe virologic and clinical outcomes following SARS-CoV infection ( Figures 2 , 4 , & 5 ).…”

“…It is well-documented that the CC can be used to model the diversity in human immune responses and disease outcomes that are not present in standard inbred mouse models ( Brinkmeyer-Langford et al, 2017 ; Elbahesh and Schughart, 2016 ; Ferris et al, 2013 ; Graham et al, 2018 ; Graham et al, 2016 ; Graham et al, 2015 ; Gralinski et al, 2015 ; Kollmus et al, 2018 ; Leist and Baric, 2018 ; Rasmussen et al, 2014 ). We have previously shown that the CC is a superior model for the vast diversity in T cell phenotypes present in the human population ( Graham et al, 2017b ), and also used a screen of F1 mice derived from CC crosses (CC recombinant intercross, CC-RIX) infected with three different RNA viruses (H1N1 influenza A virus, SARS-CoV, and West Nile virus) to reveal novel baseline immune correlates that are associated with protection from death upon infection from all of these three viruses ( Graham et al, 2020 ). Here, we focus our analysis on specific circulating, pre-infection immune phenotypes that associate with different virologic and clinical outcomes upon SARS-CoV infection, including uncontrolled virus replication in the lung, weight loss, and death.…”