Biology subjects

Businger, R.

Publications and source records attributed to Businger, R..

5 recordsLinked to original sources

bioRxiv2026

HIV-1 promotes loss of CD4+ T cell stemness and enrichment of effector-like states via Vpr-mediated TCF7 degradation

HIV-1 Vpr is abundantly packaged into virions and remodels host cells immediately after entry. Here, using high-efficiency HIV-1 infection protocols and unbiased proteomics in primary CD4+ T cells, we identify the T cell fate regulator TCF7 (TCF-1) as a previously unrecognized Vpr target. Virion-delivered Vpr rapidly depleted TCF7 in both resting and activated CD4+ T cells, which was a conserved activity of diverse Vpr proteins. The activity was independent of canonical Vpr substrate engagement but resulted terminally in proteasomal degradation of TCF7. TCF7 suppressed HIV-1 production and Env incorporation, whereas its depletion promoted loss of stem-like properties and differentiation toward effector phenotypes. Accordingly, effector T cell differentiation states are associated with productive HIV-1 infection and reduced TCF7 abundance. Thus, Vpr-mediated TCF7 depletion couples enhanced viral fitness to reprogramming of CD4+ T cell identity, generating permissive differentiated cells while impairing the maintenance of effective antiviral immunity via reduced T cell stemness.

microbiology↗

bioRxiv2023

Abemaciclib restricts HCMV replication by suppressing pUL97-mediated phosphorylation of SAMHD1

Human cytomegalovirus (HCMV) is a herpesvirus that causes life-threatening infections in newborns or immunosuppressed patients. For viral replication, HCMV establishes a network of cellular interactions, among others cyclin-dependent kinases (CDK). Furthermore, HCMV encodes pUL97, a viral kinase, which is a CDK-homologue. HCMV uses pUL97 in order to phosphorylate and thereby antagonize SAMHD1, an antiviral host cell factor. Since HCMV has several mechanisms to evade restriction by SAMHD1, we first analyzed the kinetics of SAMHD1-inactivation and found that phosphorylation of SAMHD1 by pUL97 occurs directly after infection of macrophages. We hence hypothesized that inhibition of this process qualifies as efficient antiviral target and FDA approved CDK-inhibitors (CDKIs) might be potent antivirals that prevent the inactivation of SAMHD1. Indeed, Abemaciclib, a 2nd generation CDKI exhibited superior IC50s against HCMV in infected macrophages and the antiviral activity largely relied on its ability to block pUL97-mediated SAMHD1-phosphorylation. Altogether, our study highlights the therapeutic potential of clinically-approved CDKIs as antivirals against HCMV, sheds light on their mode of action and establishes SAMHD1 as a valid and highly potent therapeutic target.

microbiology↗

bioRxiv2020

Rapid and efficient inactivation of surface dried SARS-CoV-2 by UV-C irradiation

BackgroundThe SARS-CoV-2 pandemic urges for cheap, reliable, and rapid technologies for disinfection and decontamination. One frequently proposed method is UV-C irradiation. However, UV-C doses necessary to achieve inactivation of high-titer SARS-CoV-2 are poorly defined. MethodsUsing a box and two handheld systems designed to decontaminate objects and surfaces we evaluated the efficacy of 254 nm UV-C treatment to inactivate surface dried SARS-CoV-2. ResultsDrying for two hours did not have a major impact on the infectivity of SARS-CoV-2, indicating that exhaled virus in droplets or aerosols stays infectious on surfaces at least for a certain amount of time. Short exposure of high titer surface dried virus (3-5*10^6 IU/ml) with UV-C light (16 mJ/cm2) resulted in a total inactivation of SARS-CoV-2. Dose-dependency experiments revealed that 3.5 mJ/cm2 were still effective to achieve a > 6-log reduction in viral titers whereas 1.75 mJ/cm2 lowered infectivity only by one order of magnitude. ConclusionsOur results demonstrate that SARS-CoV-2 is rapidly inactivated by relatively low doses of UV-C irradiation. Furthermore, the data reveal that the relationship between UV-C dose and log-viral titer reduction of surface residing SARS-CoV-2 is non-linear. In the context of UV-C-based technologies used to disinfect surfaces, our findings emphasize the necessity to assure sufficient and complete exposure of all relevant areas by integrated UV-C doses of at least 3.5 mJ/cm2 at 254 nm. Altogether, UV-C treatment is an effective non-chemical possibility to decontaminate surfaces from high-titer infectious SARS-CoV-2.

microbiology↗

bioRxiv2019

The human α-defensin-derived peptide HD5(1-9) inhibits cellular attachment and entry of human cytomegalovirus.

Human cytomegalovirus (HCMV) infection causes severe illness in newborns and immunocompromised patients. Since treatment options are limited there is an unmet need for new therapeutic approaches. Defensins are cationic peptides, produced by various human tissues, which serve as antimicrobial effectors of the immune system. Furthermore, some defensins are proteolytically cleaved, resulting in the generation of smaller fragments with increased activity. Together, this led us to hypothesize that defensin-derived peptides are natural human inhibitors of virus infection with low toxicity. We screened several human defensin HNP4- and HD5-derived peptides and found HD5(1-9) to be antiviral without toxicity at high concentrations. HD5(1-9) inhibited HCMV cellular attachment and thereby entry and was active against primary as well as a multiresistant HCMV isolate. Moreover, cysteine and arginine residues were identified to mediate the antiviral activity of HD5(1-9). Altogether, defensin-derived peptides, in particular HD5(1-9), qualify as promising candidates for further development as a novel class of HCMV entry inhibitors.\n\nAUTHOR SUMMARYDefensins are peptides produced by various human organs which take part in the natural defense against pathogens. Recently, it has been shown that defensins are further cleaved to smaller peptides that have high intrinsic anti-microbial activity. We here challenged the hypothesis that these peptides might have antiviral activity, and due to their presumably natural occurrence, low toxicity. Indeed, we found one peptide fragment that turned out to block the attachment of the human cytomegalovirus (HCMV) to cells. Furthermore, this peptide did not show toxicity in various cellular assays or impede the embryonic development of zebrafish at the concentrations used to block HCMV. This is important, since HCMV is one of the most important viral congenital infections. Altogether, our results hold promise for the development of a new class of antivirals against HCMV.

microbiology↗

bioRxiv2019

Platelet-neutrophil aggregates promote skin pathology in psoriasis

Psoriasis is a frequent systemic inflammatory autoimmune disease characterized primarily by skin lesions with massive infiltration of leukocytes but frequently also presents with cardiovascular comorbidities. Especially polymorphonuclear neutrophils (PMNs) abundantly infiltrate psoriatic skin but the cues that prompt PMNs to home to the skin are not well defined. To identify PMN surface receptors that may explain PMN skin homing in psoriasis patients, we screened 332 surface antigens on primary human blood PMNs from healthy donors and psoriasis patients. We identified platelet surface antigens as a defining feature of psoriasis PMNs, due to a significantly increased aggregation of neutrophils and platelets in the blood of psoriasis patients. Similarly, in the imiquimod-induced experimental in vivo model of psoriasis, disease induction promoted PMN-platelet aggregate formation. In psoriasis patients, disease directly correlated with blood platelet counts and platelets were detected in direct contact with PMNs in psoriatic but not healthy skin. Importantly, depletion of circulating platelets in vivo ameliorated disease severity significantly, indicating that the intimate relationship of PMNs and platelets may be relevant for psoriasis pathology and disease severity, and potentially for psoriasis-associated cardiovascular comorbidities. Key pointsO_LIHuman neutrophils in psoriasis patient blood show a distinct platelet signature of surface antigens C_LIO_LIPlatelets congregate with neutrophils in psoriatic skin lesions C_LIO_LICirculating platelets contribute to psoriasis skin pathology C_LI

immunology↗