Deep immune profiling of the maternal-fetal interface with mild SARS-CoV-2 infection (preprint)

Pregnant women are an at-risk group for severe COVID-19, though the majority experience mild/asymptomatic disease. Although severe COVID-19 has been shown to be associated with immune activation at the maternal-fetal interface even in the absence of active viral replication, the immune response to asymptomatic/mild COVID-19 remains unknown. Here, we assessed immunological adaptations in both blood and term decidua from 9 SARS-exposed pregnant women with asymptomatic/mild disease and 15 pregnant SARS-naive women. In addition to selective loss of tissue-resident decidual macrophages, we report attenuation of antigen presentation and type I IFN signaling but upregulation of inflammatory cytokines and chemokines in blood monocyte derived decidual macrophages. On the other hand, infection was associated with remodeling of the T cell compartment with increased frequencies of activated CD69+ tissue-resident T cells and decreased abundance of Tregs. Interestingly, frequencies of cytotoxic CD4 and CD8 T cells increased only in the blood, while CD8 effector memory T cells were expanded in the decidua. In contrast to decidual macrophages, signatures of type I IFN signaling were increased in decidual T cells. Finally, T cell receptor diversity was significantly reduced with infection in both compartments, albeit to a much greater extent in the blood. The resulting aberrant immune activation in the placenta, even with asymptomatic disease may alter the exquisitely sensitive developing fetal immune system, leading to long-term adverse outcomes for offspring.

Single cell profiling of T and B cell repertoires following SARS-CoV-2 mRNA vaccine (preprint)

mRNA based vaccines for SARS-CoV-2 have shown exceptional clinical efficacy providing robust protection against severe disease. However, our understanding of transcriptional and repertoire changes following full vaccination remains incomplete. We used single-cell RNA sequencing and functional assays to compare humoral and cellular responses to two doses of mRNA vaccine with responses observed in convalescent individuals with asymptomatic disease. Our analyses revealed enrichment of spike-specific B cells, activated CD4 T cells, and robust antigen-specific polyfunctional CD4 T cell responses in all vaccinees. On the other hand, CD8 T cell responses were both weak and variable. Interestingly, clonally expanded CD8 T cells were observed in every vaccinee, as observed following natural infection. TCR gene usage, however, was variable, reflecting the diversity of repertoires and MHC polymorphism in the human population. Natural infection induced expansion of larger CD8 T cell clones occupied distinct clusters, likely due to the recognition of a broader set of viral epitopes presented by the virus not seen in the mRNA vaccine. Our study highlights a coordinated adaptive immune response where early CD4 T cell responses facilitate the development of the B cell response and substantial expansion of effector CD8 T cells, together capable of contributing to future recall responses.

Longitudinal analyses reveal age-specific immune correlates of COVID-19 severity (preprint)

Severe COVID-19 disproportionately impacts older individuals and those with comorbidities. It is estimated that approximately 80% of COVID-19 deaths are observed among individuals >65 years of age. However, the immunological underpinnings of severe COVID-19 in the aged have yet to be defined. This study captures the longitudinal immune response to SARS-CoV-2 infection in a cohort of young and aged patients with varying disease severity. Phenotypic transcriptional and functional examination of the peripheral mononuclear cells revealed age-, time, and disease severity-specific adaptations. Gene expression signatures within memory B cells suggest qualitative differences in the antibody responses in aged patients with severe disease. Examination of T cells showed profound lymphopenia, that worsened over time and correlated with lower levels of plasma cytokines important for T cell survival in aged patients with severe disease. Single cell RNA sequencing revealed augmented signatures of activation, exhaustion, cytotoxicity, and type-I interferon signaling in memory T cells and NK cells. Although hallmarks of a cytokine storm were evident in both groups, older individuals exhibited elevated levels of chemokines that mobilize inflammatory myeloid cells, notably in those who succumbed to disease. Correspondingly, we observed a re-distribution of DC and monocytes with severe disease that was accompanied by a rewiring towards a more regulatory phenotype. Several of these critical changes, such as the reduction of surface HLA-DR on myeloid cells, were reversed in young but not aged patients over time. In summary, the data presented here provide novel insights into the impact of aging on the host response to SARS-CoV2 infection.