Infectious disease
Abstract
The role of CARD9 in the pathogenesis of various chronic fungal infections has been established; however, the precise mechanisms underlying the pathobiology of these infections remain unclear. We aimed to investigate the specific cellular mechanisms by which CARD9 deficiency contributes to the pathogenesis of chronic fungal infections. Using single-cell RNA sequencing (scRNA-seq), we analyzed the immune cell profiles in skin lesions from both murine and human samples. We focused on macrophage differentiation and signaling pathways influenced by CARD9 deficiency. We found that CARD9 deficiency promotes the differentiation of TREM2high macrophages following fungal stimulation, impairing their antifungal functions and inducing exhaustion-like T helper 1 (Th1) cells. Mechanistically, the NF-κB pathway activation was restricted in CARD9-deficient macrophages, leading to enhanced CREB activation, which in turn exerted a positive regulatory effect on Trem2 expression by activating C/EBPβ. Notably, targeting TREM2 enhanced the antifungal immune response in vivo and in vitro, thereby alleviating the severity of CARD9-deficient subcutaneous dematiaceous fungal infection. Our findings highlight the important role of CARD9 in regulating cutaneous antifungal immunity and identify potential targets for immunotherapy in chronic dematiaceous fungal infections.
Authors
Lu Zhang, Zhichun Tang, Yi Zhang, Wenjie Liu, Haitao Jiang, Li Yu, Kexin Lei, Yubo Ma, Yang-xin Fu, Ruoyu Li, Wenyan Wang, Fan Bai, Xiaowen Wang
Abstract
Influenza type A viruses (IAVs) remain an extraordinary burden to global public health and regularly circulate through human populations. This investigation describes the isolation of human mAbs from an individual with a substantial history of influenza exposure via vaccination and natural infection. From these mAbs, a clonally expanded B cell lineage was identified that recognizes the IAV neuraminidase (NA) glycoprotein and binds near the NA active site of H3N2 viruses to inhibit sialidase activity. Further characterization found that some somatically mutated members of this lineage exhibited cross-reactive binding to recombinant N1 and N9 antigens, suggesting that heterosubtypic reactivity was acquired through somatic mutation. Two candidate mAbs from this family — FluA-168 and FluA-173 — potently inhibited IAV replication in vitro and protected against lethality in vivo. The results of this study contribute to our understanding of cross-reactivity between IAV subtypes in response to diverse exposure patterns and identified 2 mAbs as potential therapeutic candidates for IAV infection.
Authors
Ty A. Sornberger, Rachael M. Wolters, Iuliia M. Gilchuk, Luke Myers, Elad Binshtein, Ryan Irving, Elaine C. Chen, Pavlo Gilchuk, Rachel S. Nargi, Rachel E. Sutton, Bethany N. Howard, Laura S. Handal, Andrew Trivette, Katherine E. Webb, Chandrahaas Kona, Eduardo Villalobos, Lauren E. Williamson, James E. Crowe Jr., Seth J. Zost
Abstract
Authors
Karen Hoffmann, Ulrike Behrendt, Peter Pennitz, Holger Kirsten, Jessica Pohl, Elena Lopez-Rodriguez, Chantal Weissfuss, Jens Kollmeier, Mario Tönnies, Sebastian Brill, Konrad Steinestel, Martin Witzenrath, Werner Wenzel, Christian Zobel, Geraldine Nouailles
Abstract
Secondary bacterial infection, often caused by Streptococcus pneumoniae (Spn), is one of the most frequent and severe complications of influenza A virus (IAV)-induced pneumonia. Phenotyping of the pulmonary immune cell landscape after IAV infection revealed a substantial depletion of the tissue-resident alveolar macrophage (TR-AM) population at day 7, which was associated with increased susceptibility to Spn outgrowth. To elucidate the molecular mechanisms underlying TR-AM depletion, and to define putative targets for treatment, we combined single-cell transcriptomics and cell-specific PCR profiling in an unbiased manner, using in vivo models of IAV infection and IAV/Spn co-infection. The TNF superfamily 14 (TNFSF14) ligand-receptor axis was revealed as the driving force behind post-influenza TR-AM death during the early infection phase, enabling the transition to pneumococcal pneumonia, while intrapulmonary transfer of genetically modified TR-AMs and antibody-mediated neutralization of specific pathway components alleviated disease severity. With a mainly neutrophilic expression and a high abundance in the bronchoalveolar fluid (BALF) of patients with severe virus-induced ARDS, TNFSF14 emerged as a key determinant of virus-driven lung injury. Targeting the TNFSF14-mediated intercellular communication network in the virus-infected lung can, therefore, improve host defense, minimizing the risk of subsequent bacterial pneumonia, and ameliorating disease outcome.
Authors
Christina Malainou, Christin Peteranderl, Maximiliano Ruben Ferrero, Ana Ivonne Vazquez-Armendariz, Ioannis Alexopoulos, Katharina Franz, Klara Knippenberg, Julian Better, Mohammad Estiri, Cheng-Yu Wu, Hendrik Schultheis, Judith Bushe, Maria-Luisa del Rio, Jose Ignacio Rodriguez-Barbosa, Klaus Pfeffer, Stefan Günther, Mario Looso, Achim Dieter Gruber, István Vadász, Ulrich Matt, Susanne Herold
Abstract
The physiology of SARS-CoV-2 virus/host interactions is not well understood. To better understand host/virus interactions, we performed a CRISPR activation screen to identify host genes that confer resistance to authentic SARS-CoV-2. This highlighted 34 new candidate genes that may alter the course of infection. We validated that 7 of these genes can suppress authentic SARS-CoV-2 infection, including the innate immune receptor P selectin, which increases SARS-CoV-2 spike-dependent binding to cells, while protecting from infection. P selectin also promotes binding to SARS-CoV-2 variants, SARS-CoV-1, and Middle East respiratory syndrome spike proteins, suggesting a general role for P selectin in highly pathogenic coronavirus infections. Importantly, P selectin protein expression driven by synthetic mRNA can block SARS-CoV-2 infection. Naturally, P selectin is expressed on platelets, and we show that it promotes spike-mediated platelet aggregation. P selectin is also expressed on the endothelium, where SARS-CoV-2 spike interactions are also P selectin dependent. In vivo, SARS-CoV-2 uses P selectin to home to capillary beds where the virus interacts with platelets and endothelium, and blocking this interaction can clear vascular-associated pulmonary SARS-CoV-2.
Authors
Cesar L. Moreno, Fernanda V.S. Castanheira, Alberto Ospina Stella, Felicity Chung, Anupriya Aggarwal, Alexander J. Cole, Lipin Loo, Alexander Dupuy, Yvonne X. Kong, Lejla Hagimola, Jemma Fenwick, Paul R. Coleman, Rebecca Carr, Tian Y. Du, Tim Ison, Michelle Newton, Maxwell P. Bui-Marinos, Scott B. Cohen, Jennifer A. Corcoran, Daniel Hesselson, Jennifer R. Gamble, Freda H. Passam, Stuart G. Turville, Paul Kubes, G. Gregory Neely
Abstract
Clonal expansion of HIV infected CD4+ T cells is a barrier to HIV eradication. We previously described a marked reduction in the frequency of the most clonally expanded infected CD4+ T cells in an individual with elite control (ES24) after initiating chemoradiation for metastatic lung cancer with a regimen that included paclitaxel and carboplatin. We tested the hypothesis that this phenomenon was due to a higher susceptibility to the chemotherapeutic drugs of CD4+ T cell clones that were sustained by proliferation. We studied a CD4+ T cell clone with replication-competent provirus integrated into the ZNF721 gene, termed ZNF721i. We stimulated the clone with its cognate peptide and then exposed the cells to paclitaxel and/or carboplatin or the antiproliferative drug, mycophenolate mofetil. While treatment of cells with the cognate peptide alone led to a marked expansion of the ZNF721i clone, treatment with the cognate peptide followed by culture with either paclitaxel or mycophenolate mofetil abrogated this process. The drugs did not affect the proliferation of other CD4+ T cell clones that were not specific for the cognate peptide. This strategy of antigen-specific stimulation followed by treatment with an antiproliferative agent may lead to the selective elimination of clonally expanded HIV-infected cells.
Authors
Filippo Dragoni, Joel Sop, Isha Gurumurthy, Tyler P. Beckey, Kellie N. Smith, Francesco R. Simonetti, Joel N. Blankson
Abstract
Mechanisms responsible for delayed wound repair are poorly understood despite the common impact of this disorder on health. To study how Staphylococcus aureus disrupts healing, mouse and human wound repair models were evaluated after exposure to S. aureus or commensal Staphylococcus. Quorum sensing by S. aureus, but not S. hominis, delayed repair and inhibited the expression of genes responsible for lipid metabolism in keratinocytes. S. aureus with inactive accessory gene regulator (agr) did not delay healing, and the inhibition of lipid metabolism was recapitulated in vitro by synthetic phenol soluble modulin α1 (psmα1) and psmα4, genes that are under agr control. However, S. aureus strains with single deletion of psmA, psmB, alpha-hemolysin (hla), or hld gene continued to delay repair, suggesting that S. aureus used multiple agr-dependent virulence factors to disrupt healing. These observations provide insight into mechanisms for delayed wound healing, identify quorum sensing as a critical event, and highlight the role of lipid biosynthesis in wound reepithelialization.
Authors
Michelle D. Bagood, Jelena Marjanovic, Nina Jiang, Hung Chan, Tatsuya Dokoshi, Kellen J. Cavagnero, Fengwu Li, Andrea Roso-Mares, Samia Almoughrabie, Edward Liu, Irena Pastar, Marjana Tomic-Canic, Alexander R. Horswill, Richard L. Gallo
Abstract
Herein, we describe a shared surface and cell wall protein, Endoglucanase 2 (Eng2), expressed on the etiological agents that cause the endemic systemic mycoses of North America – Blastomyces, Coccidioides and Histoplasma. We demonstrate that despite sequence variation of the protein across these related fungi, exposure to Eng2 vaccinates and protects inbred and humanized HLA-DR4 strains of mice against lethal experimental infections with these fungi by eliciting adaptive immunity mediated by CD4 T cells. We also show that CD4 T cell precursors against Eng2 are detectable in naïve individuals and that patients who have recovered from these infections evince a memory and recall CD4 T cell response to Eng2 and its immunodominant epitopes that we have mapped. We create and catalogue new tools and information such as immunodominant peptide epitopes of Eng2 from each fungus recognized by inbred mice and human subjects and we engineer peptide-MHC II tetramers for tracking T cells in inbred and HLA-DR4 humanized mice that will be useful for those who study these infections in mice and humans. Lastly, because most patients demonstrate memory and recall responses against Eng2, our work offers new tools for diagnosis of this collection of infectious diseases across North America.
Authors
Uju J. Okaa, Cleison Ledesma Taira, Lucas dos Santos Dias, Hannah Dobson, Gregory C. Kujoth, Althea Campuzano, E.Jane Homan, George R. Thompson, Chiung-Yu Hung, George S. Deepe, Marcel Wüthrich, Bruce S. Klein
Abstract
Bacterial infections, particularly uropathogenic E. coli (UPEC), contribute substantially to male infertility through tissue damage and subsequent fibrosis in the testis and epididymis. The role of testicular macrophages (TMs), a diverse cell population integral to tissue maintenance and immune balance, in fibrosis is not fully understood. Here, we used single-cell RNA sequencing in a murine model of epididymo-orchitis to analyze TM dynamics during UPEC infection. Our study identified a marked increase in S100a4+ macrophages, originating from monocytes, strongly associated with fibrotic changes. This association was validated in human testicular and epididymal samples. We further demonstrated that S100a4+ macrophages transition to a myofibroblast-like phenotype, producing extracellular matrix proteins such as collagen I and fibronectin. S100a4, both extracellular and intracellular, activated collagen synthesis through the TGF-β/STAT3 signaling pathway, highlighting this pathway as a therapeutic target. Inhibition of S100a4 with niclosamide or macrophage-specific S100a4 KO markedly reduced immune infiltration, tissue damage, and fibrosis in infected murine models. Our findings establish the critical role of S100a4+ macrophages in fibrosis during UPEC-induced epididymo-orchitis and propose them as potential targets for antifibrotic therapy development.
Authors
Ming Wang, Xu Chu, Zhongyu Fan, Lin Chen, Huafei Wang, Peng Wang, Zihao Wang, Yiming Zhang, Yihao Du, Sudhanshu Bhushan, Zhengguo Zhang
Abstract
Molnupiravir is an antiviral medicine that induces lethal copying errors during SARS-CoV-2 RNA replication. Molnupiravir reduced hospitalization in one pivotal trial by 50% and had variable effects on reducing viral RNA levels in three separate trials. We used mathematical models to simulate these trials and closely recapitulated their virologic outcomes. Model simulations suggest lower antiviral potency against pre-omicron SARS-CoV-2 variants than against omicron. We estimate that in vitro assays underestimate in vivo potency 6-7 fold against omicron variants. Our model suggests that because polymerase chain reaction detects molnupiravir mutated variants, the true reduction in non-mutated viral RNA is underestimated by ~0.4 log10 in the two trials conducted while omicron variants dominated. Viral area under the curve estimates differ significantly between non-mutated and mutated viral RNA. Our results reinforce past work suggesting that in vitro assays are unreliable for estimating in vivo antiviral drug potency and suggest that virologic endpoints for respiratory virus clinical trials should be catered to the drug mechanism of action.
Authors
Shadisadat Esmaeili, Katherine Owens, Ugo Avila-Ponce de Leon, Joseph F. Standing, David M. Lowe, Shengyuan Zhang, James A. Watson, William H.K. Schilling, Jessica Wagoner, Stephen J. Polyak, Joshua T. Schiffer
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ISSN: 0021-9738 (print), 1558-8238 (online)