Pathogens and Immunity最新文献

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the disease COVID-19 that has decimated the health and economy of our planet. The virus causes the disease not only in people but also in companion and wild animals. People with diabetes are at risk of the disease. As yet we do not know why the virus has been highly successful in causing the pandemic within 3 months of its first report. The structural proteins of SARS include membrane glycoprotein (M), envelope protein (E), nucleocapsid protein (N), and the spike protein (S).

Methods: The structure and function of the most abundant structural protein of SARS-CoV-2, the membrane (M) glycoprotein, is not fully understood. Using in silico analyses we determined the structure and potential function of the M protein.

Results: The M protein of SARS-CoV-2 is 98.6% similar to the M protein of bat SARS-CoV, maintains 98.2% homology with pangolin SARS-CoV, and has 90% homology with the M protein of SARS-CoV; whereas, the similarity is only 38% with the M protein of MERS-CoV. In silico analyses showed that the M protein of SARS-CoV-2 has a triple helix bundle, forms a single 3-trans-membrane domain, and is homologous to the prokaryotic sugar transport protein SemiSWEET. SemiSWEETs are related to the PQ-loop family whose members function as cargo receptors in vesicle transport, mediate movement of basic amino acids across lysosomal membranes, and are also involved in phospholipase flippase function.

Conclusions: The advantage and role of the M protein having a sugar transporter-like structure is not clearly understood. The M protein of SARS-CoV-2 interacts with S, E, and N protein. The S protein of the virus is glycosylated. It could be hypothesized that the sugar transporter-like structure of the M protein influences glycosylation of the S protein. Endocytosis is critical for the internalization and maturation of RNA viruses, including SARS-CoV-2. Sucrose is involved in endosome and lysosome maturation and may also induce autophagy, pathways that help in the entry of the virus. Overall, it could be hypothesized that the SemiSWEET sugar transporter-like structure of the M protein may be involved in multiple functions that may aid in the rapid proliferation, replication, and immune evasion of the SARS-CoV-2 virus. Biological experiments would validate the presence and function of the SemiSWEET sugar transporter.

Background: Red cell distribution width (RDW), a measure of anisocytosis, is observed in chronic inflammation and is a prognostic marker in critically ill patients without COVID-19, but data in COVID-19 are limited.

Methods: Between March 12 and April 19, 2020, 282 individuals with confirmed COVID-19 and RDW available within 7 days prior to COVID-19 confirmation were evaluated. Individuals were grouped by quartiles of RDW. Association between quartiles of RDW and mortality was assessed using the Kaplan-Meier method and statistical significance was assessed using the log-rank test. The association between RDW and all-cause mortality was further assessed using a Cox proportional hazards model. Plasma cytokine levels in uninfected ambulatory adults without cardiovascular disease (n=38) were measured and bivariate Spearman correlations and principle components analysis were used to identify relationships between cytokine concentrations with RDW.

Results: After adjusting for age, sex, race, cardiovascular disease, and hemoglobin, there was an association between RDW and mortality (Quartile 4 vs Quartile 1: HR 4.04 [1.08-15.07]), with each 1% increment in RDW associated with a 39% increased rate of mortality (HR 1.39 [1.21-1.59]). Remote RDW was also associated with mortality after COVID-19 infection. Among uninfected ambulatory adults without cardiovascular disease, RDW was associated with elevated pro-inflammatory cytokines (TNF-α, IL8, IL6, IL1b), but not regulatory cytokines (TGFb).

Conclusions: Anisocytosis predicts short-term mortality in COVID-19 patients, often predates viral exposure, and may be related to a pro-inflammatory phenotype. Additional study of whether the RDW can assist in the early identification of pending cytokine storm is warranted.

Background: Pandemic COVID-19 pneumonia due to SARS-2 is an important cause of morbidity and mortality. Emerging evidence links poor outcomes to an inflammatory cytokine storm.

Methods: We treated 89 hospitalized patients with COVID-19 pneumonia and heightened systemic inflammation (elevated serum C reactive protein and interleukin-6 levels) with an infusion of tocilizumab (TCZ), a human monoclonal IgG1 antibody to the interleukin-6 receptor.

Results: Clinical and laboratory evidence of improvement was evident when baseline and 1-2-day post-infusion indices were compared. Among the 72 patients receiving supplemental oxygen without mechanical ventilation, severity of condition on the NEWS2 scale scores fell from 5 to 2 (P<0.001), C reactive protein levels fell from 95 to 14 mg/L (P<0.001), and lymphocyte counts rose from 900 to 1000/uL (P=0.036). Sixty-three of 72 patients were discharged from the hospital, one patient died, and eight patients remained in the hospital at the time of this writing. Among the 17 patients receiving mechanical ventilation, despite a rapid decrease in CRP levels from 89 to 35 mg/L (P=0.014) and early improvements in NEWS2 scores in 10 of 17 patients, 10 patients ultimately died and the other seven remain in the hospital at the time of this writing. Overall, mortality was only seen in patients who had markedly elevated CRP levels (>30 mg/L) and low lymphocyte counts (<1000/uL) before TCZ administration.

Conclusions: Inflammation and lymphocytopenia are linked to mortality in COVID-19. Inhibition of IL-6 activity by administration of tocilizumab, an anti-IL-6 receptor antibody, is associated with rapid improvement in both CRP and lymphocyte counts and in clinical indices. Controlled clinical trials are needed to confirm the utility of IL-6 blockade in this setting. Additional interventions will be needed for patients requiring mechanical ventilation.

Background: Direct-acting antiviral (DAA) therapy among hepatitis C virus (HCV)-infected kidney transplant recipients is associated with short-term improvement in protein/creatinine (P/C) ratios, but how HCV cure affects long-term graft outcomes remains unknown.

Methods: This is a retrospective follow-up study of 59 HCV-infected patients who underwent kidney transplant at the University of Alabama at Birmingham between 2007-2015 who were followed until the end of 2017. We examined the association of DAA-induced HCV cure with graft failure or death by survival analyses (Kaplan-Meier, Cox regression).

Results: Mean age was 55 years, 73% were African American, and 68% were male. Median baseline creatinine was 1.4 mg/dL, P/C ratio was 0.5, and estimated glomerular filtration rate (eGFR) was 59 mL/min. Of those who received DAA, 24 (83%) achieved cure. The remaining 5 DAA patients (17%) did not have documented evidence of sustained virologic response (SVR). Overall, 19 (32%) patients experienced graft failure or death; with lower incidence in treated patients than untreated (4 vs 15 events; 2.6 vs 10.3 per 100 person-years [cHR 0.19, 95% CI: 0.06-0.66]). When adjusted for age, sex, race, and proteinuria, the association remained strong and invariant across time-varying (aHR 0.30, 95% CI: 0.08-1.10), time-averaged (aHR 0.28, 95% CI: 0.07-1.07), and time-varying-cumulative (aHR 0.32, 95% CI: 0.08-1.21) proteinuria metrics.

Conclusions: DAAs therapy was associated with improved graft survival and reduced mortality. While not statistically significant, the association was strong, and these single-center findings warrant larger studies to demonstrate the benefits of HCV treatment in this population.

The frequency and functions of Th17-polarized CCR6⁺RORyt⁺CD4⁺ T cells are rapidly compromised upon HIV infection and are not restored with long-term viral suppressive antiretroviral therapy (ART). In line with this, Th17 cells represent selective HIV-1 infection targets mainly at mucosal sites, with long-lived Th17 subsets carrying replication-competent HIV-DNA during ART. Therefore, novel Th17-specific therapeutic interventions are needed as a supplement of ART to reach the goal of HIV remission/cure. Th17 cells express high levels of peroxisome proliferator-activated receptor gamma (PPARy), which acts as a transcriptional repressor of the HIV provirus and the rorc gene, which encodes for the Th17-specific master regulator RORyt. Thus, we hypothesized that the pharmacological inhibition of PPARy will facilitate HIV reservoir reactivation while enhancing Th17 effector functions. Consistent with this prediction, the PPARy antagonist T0070907 significantly increased HIV transcription (cell-associated HIV-RNA) and RORyt-mediated Th17 effector functions (IL-17A). Unexpectedly, the PPARy antagonism limited HIV outgrowth from cells of ART-treated people living with HIV (PLWH), as well as HIV replication in vitro. Mechanistically, PPARy inhibition in CCR6⁺CD4⁺ T cells induced the upregulation of transcripts linked to Th17-polarisation (RORyt, STAT3, BCL6 IL-17A/F, IL-21) and HIV transcription (NCOA1-3, CDK9, HTATIP2). Interestingly, several transcripts involved in HIV-restriction were upregulated (Caveolin-1, TRIM22, TRIM5α, BST2, miR-29), whereas HIV permissiveness transcripts were downregulated (CCR5, furin), consistent with the decrease in HIV outgrowth/replication. Finally, PPARy inhibition increased intracellular HIV-p24 expression and prevented BST-2 downregulation on infected T cells, suggesting that progeny virion release is restricted by BST-2-dependent mechanisms. These results provide a strong rationale for considering PPARy antagonism as a novel strategy for HIV-reservoir purging and restoring Th17-mediated mucosal immunity in ART-treated PLWH.

Cytomegalovirus (CMV), a ubiquitous human pathogen that is never cleared from the host, has long been thought to be relatively innocuous in immunocompetent adults, but causes severe complications including blindness, end-organ disease, and death in newborns and in immuno-compromised individuals, such as organ transplant recipients and those suffering from AIDS. Yet even in persons with intact immunity, CMV infection is associated with profound stimulation of immune and inflammatory pathways. Carriers of CMV infection also have an elevated risk of developing cardiovascular complications. In this review, we define the proposed mechanisms of how CMV contributes to cardiovascular disease (CVD), describe current approaches to target CMV, and discuss how these strategies may or may not alleviate cardiovascular complications in those with CMV infection. In addition, we discuss the special situation of CMV coinfection in people with HIV infection receiving antiretroviral therapy, and describe how these 2 viral infections may interact to potentiate CVD in this especially vulnerable population.

People with HIV (PWH) experience accentuated biological aging, as defined by markers of inflammation, immune dysfunction, and the epigenetic clock. They also have an elevated risk of multiple age-associated comorbidities. To discuss current knowledge, research gaps, and priorities in aging and age-related comorbidities in treated HIV infection, the NIH program staff organized a workshop held in Bethesda, Maryland in September 2019. This review article describes highlights of discussions led by the Pathogenesis/Basic Science Research working group that focused on three high priority topics: immunopathogenesis; the microbiome/virome; and aging and senescence. We summarize knowledge in these fields and describe key questions for research on the pathogenesis of aging and age-related comorbidities in PWH. Understanding the drivers and mechanisms underlying accentuated biological aging is a high priority that will help identify potential therapeutic targets to improve healthspan in older PWH.

Background: Contaminated surfaces are a potential source for spread of respiratory viruses including SARS-CoV-2. Ultraviolet-C (UV-C) light is effective against RNA and DNA viruses and could be useful for decontamination of high-touch fomites that are shared by multiple users.

Methods: A modification of the American Society for Testing and Materials standard quantitative carrier disk test method (ASTM E-2197-11) was used to examine the effectiveness of UV-C light for rapid decontamination of plastic airport security bins inoculated at 3 sites with methicillin-resistant Staphylococcus aureus (MRSA) and bacteriophages MS2, PhiX174, and Phi6, an enveloped RNA virus used as a surrogate for coronaviruses. Reductions of 3 log₁₀ on inoculated plastic bins were considered effective for decontamination.

Results: UV-C light administered as 10-, 20-, or 30-second cycles in proximity to a plastic bin reduced contamination on each of the test sites, including vertical and horizontal surfaces. The 30-second cycle met criteria for decontamination of all 3 test sites for all the test organisms except bacteriophage MS2 which was reduced by greater than 2 log₁₀ PFU at each site.

Conclusions: UV-C light is an attractive technology for rapid decontamination of airport security bins. Further work is needed to evaluate the utility of UV-C light in real-world settings and to develop methods to provide automated movement of bins through a UV-C decontamination process.

In most HIV-infected persons, the natural history of untreated infection is one of sustained viremia, progressive CD4 T cell depletion with resultant morbidity and mortality. The advent of effective combination antiretroviral therapy (ART) that controls HIV replication has altered this landscape dramatically. Yet a rare population of HIV-infected persons-elite controllers (EC)-can control HIV replication such that plasma levels of virus are "undetectable" without ART. The EC phenotype is heterogeneous, with some subjects durably controlling the virus-persistent elite controllers-and some eventually losing viral control-transient elite controllers. Overall, EC tend to have robust HIV-specific T cell responses and in some cases, mainly in transient elite controllers, elevated activation and inflammation indices that diminish with ART suggesting that endogenous defenses against this persistent pathogen come at the cost of heightened activation/inflammation. A limited data set suggests that cardiovascular disease risk as well as the occur-rence of other morbid events may be greater in the overall EC population than in treated HIV infection. ART in EC decreases activation indices but does not appear to increase circulating CD4 T cell numbers nor do we know if it alters clinical outcomes. Thus, it is difficult to recommend or discourage a decision to start ART in the EC population but the authors lean toward treatment particularly in those EC whose activation indices are high and those who are progressively losing circulating CD4 T cell numbers. Biomarkers that can reliably predict loss of virologic control and immune failure are needed.