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. 2020 Mar 2;221(6):882-889.
doi: 10.1093/infdis/jiz531.

Immune Predictors of Mortality After Ribonucleic Acid Virus Infection

Jessica B Graham  1 , Jessica L Swarts  1 , Vineet D Menachery  2   3 , Lisa E Gralinski  2 , Alexandra Schäfer  2 , Kenneth S Plante  4 , Clayton R Morrison  4 , Kathleen M Voss  5 , Richard Green  5 , Gabrielle Choonoo  6 , Sophia Jeng  6 , Darla R Miller  4 , Michael A Mooney  6   7 , Shannon K McWeeney  6   7   8 , Martin T Ferris  4 , Fernando Pardo-Manuel de Villena  4   9 , Michael Gale  5 , Mark T Heise  4   9 , Ralph S Baric  2 , Jennifer M Lund  1   10
Affiliations

Immune Predictors of Mortality After Ribonucleic Acid Virus Infection

Jessica B Graham et al. J Infect Dis. .

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, severe acute respiratory syndrome-coronavirus, and West Nile virus.

Results: The CC mice exhibited a range of disease manifestations upon infections, and we used this natural variation to identify strains with mortality after infection and strains exhibiting no mortality. We then used comprehensive preinfection 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.

Keywords: Collaborative Cross; RNA virus infection; immune correlates of mortality.

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Figures

Figure 1.
Figure 1.
A distinct baseline T-cell ratio and activation signature associates with protection from mortality after virus infections. Age-matched male or female CC-RIX were infected with H1N1 influenza, severe acute respiratory syndrome-coronavirus, or West Nile virus and monitored for survival. Based on these data, they were grouped into “No Mortality” or “Mortality in all 3” categories as shown in Table 1. A second cohort of 3–6 age-matched male mice of the same CC-RIX were euthanized, and splenic cells were analyzed by flow cytometry staining to determine the CD4:CD8 T-cell ratio, the frequency of CD3+ T-cells, the frequency of CD3+ T cells that were CD8+ or CD4+ (A), and the frequency of CD44+CD8 T cells (B), CD44+CD4 T cells (C), CXCR3+CD8 T cells (D), CD62L−CD4 T cells (E), Ki67+CD4 T cells (F), Tbet+CD8 T cells (G), Tbet+CD4 T cells (H), and inducible costimulator (ICOS)+ CD4 T cells (I). Statistical significance was determined by Mann-Whitney test.
Figure 2.
Figure 2.
An increased frequency of regulatory T cells (Tregs) at steady-state predicts protection from death after subsequent virus infections. Age-matched male or female CC-RIX were infected with H1N1 influenza, severe acute respiratory syndrome-coronavirus, or West Nile virus and monitored for survival. Based on these data, they were grouped into “No Mortality” or “Mortality in all 3” categories as shown in Table 1. A second cohort of 3–6 age-matched male mice of the same CC-RIX were euthanized, and splenic cells were analyzed by flow cytometry staining to determine the frequency of Foxp3+ Tregs (A), CD44+ Tregs (B), glucocorticoid-induced tumor necrosis factor receptor (GITR)+ Tregs (C), and CD25+ Tregs (D). Statistical significance was determined by Mann-Whitney test.
Figure 3.
Figure 3.
Enhanced T cell-mediated proinflammatory cytokine potential at baseline is associated with risk of death after virus infections. Age-matched male or female CC-RIX were infected with H1N1 influenza, severe acute respiratory syndrome-coronavirus, or West Nile virus and monitored for survival. Based on these data, they were grouped into “No Mortality” or “Mortality in all 3” categories as shown in Table 1. A second cohort of 3–6 age-matched male mice of the same CC-RIX were euthanized, and splenic cells were treated with anti-CD3/CD28 for intracellular cytokine staining assessment of interferon (IFN)γ (A and D), interleukin (IL)-17 (B and E), and tumor necrosis factor (TNF)α (C and F) expression by CD8 (A–C) and CD4 (D–F) T cells. Statistical significance was determined by Mann-Whitney test.
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