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Clostridia isolated from helminth-colonized humans promote the life cycle of Trichuris species

Sargsian, Shushan; Chen, Ze; Lee, Soo Ching; Robertson, Amicha; Thur, Rafaela Saes; Sproch, Julia; Devlin, Joseph C; Tee, Mian Zi; Er, Yi Xian; Copin, Richard; Heguy, Adriana; Pironti, Alejandro; Torres, Victor J; Ruggles, Kelly V; Lim, Yvonne A L; Bethony, Jeffrey; Loke, P'ng; Cadwell, Ken
Soil-transmitted intestinal worms known as helminths colonize over 1.5 billion people worldwide. Although helminth colonization has been associated with altered composition of the gut microbiota, such as increases in Clostridia, individual species have not been isolated and characterized. Here, we isolate and sequence the genome of 13 Clostridia from the Orang Asli, an indigenous population in Malaysia with a high prevalence of helminth infections. Metagenomic analysis of 650 fecal samples from urban and rural Malaysians confirm the prevalence of species corresponding to these isolates and reveal a specific association between Peptostreptococcaceae family members and helminth colonization. Remarkably, Peptostreptococcaceae isolated from the Orang Asli display superior capacity to promote the life cycle of whipworm species, including hatching of eggs from Trichuris muris and Trichuris trichiura. These findings support a model in which helminths select for gut colonization of microbes that support their life cycle.
PMID: 36450245
ISSN: 2211-1247
CID: 5374022

The influenza-injured lung microenvironment promotes MRSA virulence, contributing to severe secondary bacterial pneumonia

Langouët-Astrié, Christophe; Oshima, Kaori; McMurtry, Sarah A; Yang, Yimu; Kwiecinski, Jakub M; LaRivière, Wells B; Kavanaugh, Jeffrey S; Zakharevich, Igor; Hansen, Kirk C; Shi, Deling; Zhang, Fuming; Boguslawski, Kristina M; Perelman, Sofya S; Su, Gouwei; Torres, Victor J; Liu, Jian; Horswill, Alexander R; Schmidt, Eric P
Influenza infection is substantially worsened by the onset of secondary pneumonia caused by bacteria, such as methicillin-resistant Staphylococcus aureus (MRSA). The bidirectional interaction between the influenza-injured lung microenvironment and MRSA is poorly understood. By conditioning MRSA ex vivo in bronchoalveolar lavage fluid collected from mice at various time points of influenza infection, we found that the influenza-injured lung microenvironment dynamically induces MRSA to increase cytotoxin expression while decreasing metabolic pathways. LukAB, a SaeRS two-component system-dependent cytotoxin, is particularly important to the severity of post-influenza MRSA pneumonia. LukAB's activity is likely shaped by the post-influenza lung microenvironment, as LukAB binds to (and is activated by) heparan sulfate (HS) oligosaccharide sequences shed from the epithelial glycocalyx after influenza. Our findings indicate that post-influenza MRSA pneumonia is shaped by bidirectional host-pathogen interactions: host injury triggers changes in bacterial expression of toxins, the activity of which may be shaped by host-derived HS fragments.
PMID: 36450248
ISSN: 2211-1247
CID: 5374032

Defensosomes: a new role for autophagy proteins in innate immune defense

Ching, Krystal L; Torres, Victor J; Cadwell, Ken
In recent years, the contribution of exosomes to immunity, inflammation and host-pathogen interaction have been appreciated. Exosomes are small secreted extracellular vesicles from endosomal origin that contain a myriad of cellular molecules (protein, nucleic acids), including surface receptors. We have reported a pathogen-induced and macroautophagy/autophagy-dependent class of exosomes coined as "defensosomes", which protect the host from membrane-targeting toxins. In a recent study, we found that defensosomes decorated with ACE2, the SARS-CoV-2 cellular receptor, are produced in the lungs of patients with COVID-19, and that increased concentration of ACE2-loaded defensosomes is associated with decreased hospitalization length. Mechanistically, SARS-CoV-2 induces the production of ACE2-coated defensosomes, a process requiring the autophagy machinery, which in turn binds and neutralizes the virus. We propose that defensosomes represent a new form of autophagy-mediated innate immunity that contributes to the host's armamentarium against pathogens.
PMID: 36409156
ISSN: 1554-8635
CID: 5371952

Gut microbiome dysbiosis in antibiotic-treated COVID-19 patients is associated with microbial translocation and bacteremia

Bernard-Raichon, Lucie; Venzon, Mericien; Klein, Jon; Axelrad, Jordan E; Zhang, Chenzhen; Sullivan, Alexis P; Hussey, Grant A; Casanovas-Massana, Arnau; Noval, Maria G; Valero-Jimenez, Ana M; Gago, Juan; Putzel, Gregory; Pironti, Alejandro; Wilder, Evan; Thorpe, Lorna E; Littman, Dan R; Dittmann, Meike; Stapleford, Kenneth A; Shopsin, Bo; Torres, Victor J; Ko, Albert I; Iwasaki, Akiko; Cadwell, Ken; Schluter, Jonas
Although microbial populations in the gut microbiome are associated with COVID-19 severity, a causal impact on patient health has not been established. Here we provide evidence that gut microbiome dysbiosis is associated with translocation of bacteria into the blood during COVID-19, causing life-threatening secondary infections. We first demonstrate SARS-CoV-2 infection induces gut microbiome dysbiosis in mice, which correlated with alterations to Paneth cells and goblet cells, and markers of barrier permeability. Samples collected from 96 COVID-19 patients at two different clinical sites also revealed substantial gut microbiome dysbiosis, including blooms of opportunistic pathogenic bacterial genera known to include antimicrobial-resistant species. Analysis of blood culture results testing for secondary microbial bloodstream infections with paired microbiome data indicates that bacteria may translocate from the gut into the systemic circulation of COVID-19 patients. These results are consistent with a direct role for gut microbiome dysbiosis in enabling dangerous secondary infections during COVID-19.
PMID: 36319618
ISSN: 2041-1723
CID: 5358262

The tempo and mode of gene regulatory programs during bacterial infection

Avital, Gal; Kuperwaser, Felicia; Pountain, Andrew W; Lacey, Keenan A; Zwack, Erin E; Podkowik, Magdalena; Shopsin, Bo; Torres, Victor J; Yanai, Itai
Innate immune recognition of bacterial pathogens is a key determinant of the ensuing systemic response, and host or pathogen heterogeneity in this early interaction can impact the course of infection. To gain insight into host response heterogeneity, we investigate macrophage inflammatory dynamics using primary human macrophages infected with Group B Streptococcus. Transcriptomic analysis reveals discrete cellular states within responding macrophages, one of which consists of four sub-states, reflecting inflammatory activation. Infection with six additional bacterial species-Staphylococcus aureus, Listeria monocytogenes, Enterococcus faecalis, Yersinia pseudotuberculosis, Shigella flexneri, and Salmonella enterica-recapitulates these states, though at different frequencies. We show that modulating the duration of infection and the presence of a toxin impacts inflammatory trajectory dynamics. We provide evidence for this trajectory in infected macrophages in an in vivo model of Staphylococcus aureus infection. Our cell-state analysis defines a framework for understanding inflammatory activation dynamics in response to bacterial infection.
PMID: 36223751
ISSN: 2211-1247
CID: 5352072

ACE2-containing defensosomes serve as decoys to inhibit SARS-CoV-2 infection

Ching, Krystal L; de Vries, Maren; Gago, Juan; Dancel-Manning, Kristen; Sall, Joseph; Rice, William J; Barnett, Clea; Khodadadi-Jamayran, Alireza; Tsirigos, Aristotelis; Liang, Feng-Xia; Thorpe, Lorna E; Shopsin, Bo; Segal, Leopoldo N; Dittmann, Meike; Torres, Victor J; Cadwell, Ken
Extracellular vesicles of endosomal origin, exosomes, mediate intercellular communication by transporting substrates with a variety of functions related to tissue homeostasis and disease. Their diagnostic and therapeutic potential has been recognized for diseases such as cancer in which signaling defects are prominent. However, it is unclear to what extent exosomes and their cargo inform the progression of infectious diseases. We recently defined a subset of exosomes termed defensosomes that are mobilized during bacterial infection in a manner dependent on autophagy proteins. Through incorporating protein receptors on their surface, defensosomes mediated host defense by binding and inhibiting pore-forming toxins secreted by bacterial pathogens. Given this capacity to serve as decoys that interfere with surface protein interactions, we investigated the role of defensosomes during infection by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the etiological agent of Coronavirus Disease 2019 (COVID-19). Consistent with a protective function, exosomes containing high levels of the viral receptor ACE2 in bronchoalveolar lavage fluid (BALF) from critically ill COVID-19 patients was associated with reduced intensive care unit (ICU) and hospitalization times. We found ACE2+ exosomes were induced by SARS-CoV-2 infection and activation of viral sensors in cell culture, which required the autophagy protein ATG16L1, defining these as defensosomes. We further demonstrate that ACE2+ defensosomes directly bind and block viral entry. These findings suggest that defensosomes may contribute to the antiviral response against SARS-CoV-2 and expand our knowledge on the regulation and effects of extracellular vesicles during infection.
PMID: 36099266
ISSN: 1545-7885
CID: 5335192

Staphylococcus aureus induces a muted host response in human blood that blunts the recruitment of neutrophils

Zwack, Erin E; Chen, Ze; Devlin, Joseph C; Li, Zhi; Zheng, Xuhui; Weinstock, Ada; Lacey, Keenan A; Fisher, Edward A; Fenyö, David; Ruggles, Kelly V; Loke, P'ng; Torres, Victor J
PMID: 35881802
ISSN: 1091-6490
CID: 5276372

Structural basis for inhibition of the drug efflux pump NorA from Staphylococcus aureus

Brawley, Douglas N; Sauer, David B; Li, Jianping; Zheng, Xuhui; Koide, Akiko; Jedhe, Ganesh S; Suwatthee, Tiffany; Song, Jinmei; Liu, Zheng; Arora, Paramjit S; Koide, Shohei; Torres, Victor J; Wang, Da-Neng; Traaseth, Nathaniel J
Membrane protein efflux pumps confer antibiotic resistance by extruding structurally distinct compounds and lowering their intracellular concentration. Yet, there are no clinically approved drugs to inhibit efflux pumps, which would potentiate the efficacy of existing antibiotics rendered ineffective by drug efflux. Here we identified synthetic antigen-binding fragments (Fabs) that inhibit the quinolone transporter NorA from methicillin-resistant Staphylococcus aureus (MRSA). Structures of two NorA-Fab complexes determined using cryo-electron microscopy reveal a Fab loop deeply inserted in the substrate-binding pocket of NorA. An arginine residue on this loop interacts with two neighboring aspartate and glutamate residues essential for NorA-mediated antibiotic resistance in MRSA. Peptide mimics of the Fab loop inhibit NorA with submicromolar potency and ablate MRSA growth in combination with the antibiotic norfloxacin. These findings establish a class of peptide inhibitors that block antibiotic efflux in MRSA by targeting indispensable residues in NorA without the need for membrane permeability.
PMID: 35361990
ISSN: 1552-4469
CID: 5201392

Microbiome-Independent Effects of Antibiotics in a Murine Model of Nosocomial Infections

Lacey, Keenan A; Gonzalez, Sandra; Yeung, Frank; Putzel, Gregory; Podkowik, Magdalena; Pironti, Alejandro; Shopsin, Bo; Cadwell, Ken; Torres, Victor J
Methicillin-resistant Staphylococcus aureus (MRSA) is one of the most common causes of hospital-acquired pneumonia. To better manage patients with MRSA pneumonia, we require a greater understanding of the host-pathogen interactions during infection. MRSA research focuses on highly virulent and cytotoxic strains, which demonstrate robust phenotypes in animal models of infection. However, nosocomial infections are often caused by hospital-acquired MRSA (HA-MRSA) isolates that exhibit low cytotoxicity and few or no phenotypes in mice, thereby confounding mechanistic studies of pathogenesis. Consequently, virulence pathways utilized by HA-MRSA in nosocomial pneumonia are largely unknown. Here, we report that conditioning mice with broad-spectrum antibiotics lowers the barrier to pneumonia, thereby transforming otherwise avirulent HA-MRSA isolates into lethal pathogens. HA-MRSA isolates are avirulent in gnotobiotic mice, mimicking results in conventional animals. Thus, the observed enhanced susceptibility to infection in antibiotic-treated mice is not due to depletion of the microbiota. More generally, we found that antibiotic conditioning leads to increased susceptibility to infection by diverse antimicrobial-resistant (AMR) pathogens of low virulence. Treatment with antibiotics leads to dehydration and malnutrition, suggesting a potential role for these clinically relevant and reducible hospital complications in susceptibility to pathogens. In sum, the model described here mitigates the impact of low virulence in immunocompetent mice, providing a convenient model to gain fundamental insight into the pathogenesis of nosocomial pathogens. IMPORTANCE Antimicrobial-resistant (AMR) pathogens are responsible for over 2.8 million infections and over 35,000 deaths per year in the United States. To study these microbes, animal models that are susceptible to these pathogens are required. However, many of these pathogens exhibit low virulence in conventional mice, which has negatively impacted mechanistic studies. Here, we show that mice treated with antibiotics in their drinking water become exquisitely susceptible to low-virulence AMR pathogens. Surprisingly, the increased susceptibility was independent of the impact of antibiotics on the microbiome and seems to be due to an unintended consequence of antibiotic treatment: weight loss due to dehydration and caloric restriction. Unlike other models used to sensitize mice to low-virulence pathogens, our model does not reduce phagocyte numbers. Thus, here, we describe an immunocompetent mouse model to facilitate the identification of novel targets and accelerate the development of preventives and therapeutics to combat infections by AMR pathogens.
PMID: 35612285
ISSN: 2150-7511
CID: 5277522

Human OTULIN haploinsufficiency impairs cell-intrinsic immunity to staphylococcal α-toxin

Spaan, András N; Neehus, Anna-Lena; Laplantine, Emmanuel; Staels, Frederik; Ogishi, Masato; Seeleuthner, Yoann; Rapaport, Franck; Lacey, Keenan A; Van Nieuwenhove, Erika; Chrabieh, Maya; Hum, David; Migaud, Mélanie; Izmiryan, Araksya; Lorenzo, Lazaro; Kochetkov, Tatiana; Heesterbeek, Dani A C; Bardoel, Bart W; DuMont, Ashley L; Dobbs, Kerry; Chardonnet, Solenne; Heissel, Søren; Baslan, Timour; Zhang, Peng; Yang, Rui; Bogunovic, Dusan; Wunderink, Herman F; Haas, Pieter-Jan A; Molina, Henrik; Van Buggenhout, Griet; Lyonnet, Stanislas; Notarangelo, Luigi D; Seppänen, Mikko R J; Weil, Robert; Seminario, Gisela; Gomez-Tello, Héctor; Wouters, Carine; Mesdaghi, Mehrnaz; Shahrooei, Mohammad; Bossuyt, Xavier; Sag, Erdal; Topaloglu, Rezan; Ozen, Seza; Leavis, Helen L; van Eijk, Maarten M J; Bezrodnik, Liliana; Blancas Galicia, Lizbeth; Hovnanian, Alain; Nassif, Aude; Bader-Meunier, Brigitte; Neven, Bénédicte; Meyts, Isabelle; Schrijvers, Rik; Puel, Anne; Bustamante, Jacinta; Aksentijevich, Ivona; Kastner, Daniel L; Torres, Victor J; Humblet-Baron, Stéphanie; Liston, Adrian; Abel, Laurent; Boisson, Bertrand; Casanova, Jean-Laurent
The molecular basis of interindividual clinical variability upon infection with Staphylococcus aureus is unclear. We describe patients with haploinsufficiency for the linear deubiquitinase OTULIN, encoded by a gene on chromosome 5p. Patients suffer from episodes of life-threatening necrosis, typically triggered by S. aureus infection. The disorder is phenocopied in patients with the 5p- (Cri-du-Chat) chromosomal deletion syndrome. OTULIN haploinsufficiency causes an accumulation of linear ubiquitin in dermal fibroblasts, but tumor necrosis factor receptor-mediated nuclear factor κB signaling remains intact. Blood leukocyte subsets are unaffected. The OTULIN-dependent accumulation of caveolin-1 in dermal fibroblasts, but not leukocytes, facilitates the cytotoxic damage inflicted by the staphylococcal virulence factor α-toxin. Naturally elicited antibodies against α-toxin contribute to incomplete clinical penetrance. Human OTULIN haploinsufficiency underlies life-threatening staphylococcal disease by disrupting cell-intrinsic immunity to α-toxin in nonleukocytic cells.
PMID: 35587511
ISSN: 1095-9203
CID: 5277492