Key Points Question What are the risk factors associated with hospitalization, mechanical ventilation, and death among patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection? Findings In this national cohort study of 88 747 veterans tested for SARS-CoV-2, hospitalization, mechanical ventilation, and mortality were significantly higher in patients with positive SARS-CoV-2 test results than among those with negative test results. Significant risk factors for mortality included older age, high regional coronavirus disease 2019 burden, higher Charlson Comorbidity Index score, fever, dyspnea, and abnormal results in many routine laboratory tests; however, obesity, Black race, Hispanic ethnicity, chronic obstructive pulmonary disease, hypertension, and smoking were not associated with mortality. Meaning In this study, most deaths from SARS-CoV-2 occurred in patients with age of 50 years or older, male sex, and greater comorbidity burden.

Composition of central nervous system lipoproteins affects the metabolism of lipoprotein constituents within the brain. The ⑀4 allele of apolipoprotein E (apoE) is a risk factor for Alzheimer's disease via an unknown mechanism(s). As glia are the primary central nervous system cell type that synthesize apoE, we characterized lipoproteins secreted by astrocytes from wild type (WT), apoE (؊/؊), and apoE transgenic mice expressing human apoE3 or apoE4 in a mouse apoE (؊/؊) background. Nondenaturing size exclusion chromatography demonstrates that WT, apoE3, and apoE4 astrocytes secrete particles the size of plasma high density lipoprotein (HDL) composed of phospholipid, free cholesterol, and protein, primarily apoE and apoJ. However, the lipid:apoE ratio of particles containing human apoE is significantly lower than WT. ApoE localizes across HDL-like particle sizes. ApoJ localizes to the smallest HDL-like particles. ApoE (؊/؊) astrocytes secrete little phospholipid or free cholesterol despite comparable apoJ expression, suggesting that apoE is required for normal secretion of astrocyte lipoproteins. Further, particles were not detected in apoE (؊/؊) samples by electron microscopy. Nondenaturing immunoprecipitation experiments indicate that apoE and apoJ reside predominantly on distinct particles. These studies suggest that apoE expression influences the unique structure of astrocyte lipoproteins, a process further modified by apoE species.The composition and type of lipoproteins present in the brain have implications not only for lipid delivery but also for the transport of apolipoprotein (apo) 1 and other lipoprotein constituents within the central nervous system (CNS). Glia, in particular astrocytes, are the primary cell type in the CNS that synthesize apoE (1, 2), whereas apoJ is expressed by astrocytes and neurons (3-5). We have previously observed that primary rat astrocytes secrete discoidal particles the size of large plasma high density lipoproteins (HDLs) that contain apoE and apoJ (6). As a ligand for lipoprotein receptors, apoE helps to regulate plasma lipid and cholesterol metabolism. This process may also be operating in the parenchyma of the brain, as neural cells express a variety of receptors in the low density lipoprotein receptor family (7-10). The role of apoJ in lipid transport in both the periphery and within the CNS is less clear, and gp330 (megalin), the only known receptor for mammalian apoJ (11), appears to be expressed only by ependymal and endothelial cells in the brain (12, 13). Thus, lipoprotein secretion by isolated glial cells may provide a system in which to further dissect the role of apoE and apoJ in lipoprotein synthesis, secretion and function in the brain. In terms of function, several lines of evidence suggest that apoE and apoJ may be involved in neural homeostasis beyond their capacity to transport lipid. Both apoE and apoJ increase in response to different brain insults (3, 14 -16). In addition, apoE and apoJ may play a role in the pathogenesis of Alzheimer's disease (AD), as...

Tuberculosis, one of the leading causes of death worldwide, stimulates inflammatory responses with beneficial and pathologic consequences. The regulation and nature of an optimal inflammatory response to Mycobacterium tuberculosis (MTb) remains poorly understood in humans. Insight into mechanisms of negative regulation of the Toll-like Receptor (TLR)-mediated innate immune response to MTb could provide significant breakthroughs in the design of new vaccines and drugs. We hypothesized that TOLLIP and its common variants negatively regulate TLR signaling in human monocytes and are associated with susceptibility to tuberculosis. Using shRNA knockdown of TOLLIP in peripheral blood human monocytes, we found that TOLLIP suppresses TNF and IL-6 production after stimulation with TLR2 and TLR4 ligands. In contrast, secretion of the anti-inflammatory cytokine IL-10 was induced by TOLLIP. We also discovered 2 common polymorphisms that are associated with either decreased levels of mRNA expression (rs3750920) or increased IL-6 production (rs5743899) in a sample of 56 healthy volunteers. Furthermore, in a case-population study in Vietnam with 760 cord-blood samples and 671 TB case patients, we found that SNPs rs3750920 and rs5743899 were associated with susceptibility to tuberculosis (p=7.03×10−16, 6.97×10−7, respectively). Together, these data demonstrate that TOLLIP has an anti-inflammatory effect on TLR signaling in humans and that TOLLIP deficiency is associated with an increased risk of TB. To our knowledge, these data also show the first associations of TOLLIP polymorphisms with any infectious disease. These data also implicate an unexpected mechanism of negative regulation of TLR signaling in human TB pathogenesis.

CpG oligodeoxynucleotides (ODN) have potent effects on innate and adaptive cellular immune responses. In this report, the ability of CpG ODN to confer long-term immunity and protection when used as a vaccine adjuvant with a clinical grade of leishmanial antigen, autoclaved Leishmania major (ALM), or a recombinant leishmanial protein was studied. In two different mouse models of L. major infection, vaccination with ALM plus CpG ODN was able to control infection and markedly reduce lesion development in susceptible BALB/c and resistant C57BL/6 (B6) mice, respectively, up to 12 wk after immunization. Moreover, B6 mice immunized with ALM plus CpG ODNs were still protected against infectious challenge even 6 mo after vaccination. In terms of immune correlates of protection, ALM plus CpG ODN-vaccinated mice displayed L. major–specific T helper cell 1 and CD8+ responses. In addition, complete protection was markedly abrogated in mice depleted of CD8+ T cells at the time of vaccination. Similarly, mice vaccinated with a recombinant leishmanial protein plus CpG ODN also had long-term protection that was dependent on CD8+ T cells in vivo. Together, these data demonstrate that CpG ODN, when used as a vaccine adjuvant with either a recombinant protein or heat-killed leishmanial antigen, can induce long-term protection against an intracellular infection in a CD8-dependent manner.