Rothchild, A. | Search bioRxiv

bioRxiv2020

Multiomic Immunophenotyping of COVID-19 Patients Reveals Early Infection Trajectories

Host immune responses play central roles in controlling SARS-CoV2 infection, yet remain incompletely characterized and understood. Here, we present a comprehensive immune response map spanning 454 proteins and 847 metabolites in plasma integrated with single-cell multi-omic assays of PBMCs in which whole transcriptome, 192 surface proteins, and T and B cell receptor sequence were co-analyzed within the context of clinical measures from 50 COVID19 patient samples. Our study reveals novel cellular subpopulations, such as proliferative exhausted CD8+ and CD4+ T cells, and cytotoxic CD4+ T cells, that may be features of severe COVID-19 infection. We condensed over 1 million immune features into a single immune response axis that independently aligns with many clinical features and is also strongly associated with disease severity. Our study represents an important resource towards understanding the heterogeneous immune responses of COVID-19 patients and may provide key information for informing therapeutic development.

immunology↗

bioRxiv2019

Latent Mycobacterium tuberculosis infection provides protection for the host by changing the activation state of the innate immune system

An efficacious vaccine against adult tuberculosis (TB) remains elusive. Progress is hampered by an incomplete understanding of the immune mechanisms that protect against infection with Mycobacterium tuberculosis (Mtb), the causative agent of TB1. Over 90% of people who become infected with Mtb mount an immune response that contains the bacteria indefinitely, leading to a state known as "latent TB infection" (LTBI)2. A significant body of epidemiologic evidence indicates that LTBI protects against active TB after re-exposure, offering an intriguing avenue to identifying protective mechanisms3, 4. We show that in a mouse model, LTBI is highly protective against infection with Mtb for up to 100 days following aerosol challenge. LTBI mice are also protected against heterologous bacterial challenge (Listeria monocytogenes) and disseminated melanoma suggesting that protection is in part mediated by alterations in the activation state of the innate immune system. Protection is associated with elevated activation of alveolar macrophages (AM), the first cells that respond to inhaled Mtb, and accelerated recruitment of Mtb-specific T cells to the lung parenchyma upon aerosol challenge. Systems approaches, including transcriptome analysis of both naive and infected AMs, as well as ex vivo functional assays, demonstrate that LTBI reconfigures the response of tissue resident AMs.. Furthermore, we demonstrate that both LTBI mice and latently infected humans show similar alterations in the relative proportions of circulating innate immune cells, suggesting that the same cellular changes observed in the LTBI mouse model are also occurring in humans. Therefore, we argue that under certain circumstances, LTBI could be beneficial to the host by providing protection against subsequent Mtb exposure.

immunology↗