Infectious disease
Abstract
We recently described the evolution of a community-acquired methicillin-resistant Staphylococcus aureus (CA-MRSA) USA300 variant responsible for an outbreak of skin and soft tissue infections. Acquisition of a mosaic version of the Φ11 prophage (mΦ11) that increases skin abscess size was an early step in CA-MRSA adaptation that primed the successful spread of the clone. The present report shows how prophage mΦ11 exerts its effect on virulence for skin infection without encoding a known toxin or fitness genes. Abscess size and skin inflammation were associated with DNA methylase activity of an mΦ11-encoded adenine methyltransferase (designated pamA). pamA increased expression of fibronectin-binding protein A (fnbA; FnBPA), and inactivation of fnbA eliminated the effect of pamA on abscess virulence without affecting strains lacking pamA. Thus, fnbA is a pamA-specific virulence factor. Mechanistically, pamA was shown to promote biofilm formation in vivo in skin abscesses, a phenotype linked to FnBPA’s role in biofilm formation. Collectively, these data reveal a critical mechanism—epigenetic regulation of staphylococcal gene expression—by which phage can regulate virulence to drive adaptive leaps by S. aureus.
Authors
Robert J. Ulrich, Magdalena Podkowik, Rebecca Tierce, Irnov Irnov, Gregory Putzel, Nora M. Samhadaneh, Keenan A. Lacey, Daiane Boff, Sabrina M. Morales, Sohei Makita, Theodora K. Karagounis, Erin E Zwack, Chunyi Zhou, Randie H. Kim, Karl Drlica, Alejandro Pironti, Harm van Bakel, Victor J. Torres, Bo Shopsin
Abstract
HIV infection accelerates biological aging, but the contribution of the host’s age to this process is unknown. We investigated the influence of SIV infection in macaques (SIVmac) on the risk of comorbidities and aging in young and old rhesus macaques (RMs) by assessing pathogenesis markers, DNA methylation–based epigenetic age (EA), and EA acceleration (EAA) in blood and tissues. Initially, upon SIV infection, the young RMs showed greater resilience to CD4+ T cell depletion, better control of T cell activation, hypercoagulation, and excessive inflammation, yet this resilience was progressively lost in the advanced stages of infection. During the late stages of infection, the young RMs, but not the aged ones, showed an increase in EA in PBMCs; also, EAA in the cerebellum and heart of young RMs was higher compared with old RMs. SIV infection was more pathogenic in aged animals in early stages, leading to a more rapid disease progression; however, accelerated aging mostly affected young animals, so that the levels of multiple key pathogenesis markers in the young RMs converged toward those specific to aged ones in the late stages of infection. We conclude that SIV infection–driven age acceleration is tissue specific, and that host age influences the susceptibility of different tissues to enhanced aging.
Authors
Anna J. Jasinska, Ranjit Sivanandham, Sindhuja Sivanandham, Cuiling Xu, Juozas Gordevicius, Milda Milčiūtė, Robert T. Brooke, Paola Sette, Tianyu He, Egidio Brocca-Cofano, Benjamin B. Policicchio, Krishna Nayak, Saharsh Talwar, Haritha Annapureddy, Dongzhu Ma, Ruy M. Ribeiro, Cristian Apetrei, Ivona Pandrea
Abstract
Although virus-like particle (VLPs) vaccines were shown to be effective against several viruses, their advantage over vaccines which include envelope protein only is not completely clear, particularly for mRNA-encoded VLPs. We conducted a side-by-side comparison of the immunogenicity and protective efficacy of mRNA vaccines encoding for the Marburg virus (MARV) full-length GP delivered alone or as a VLP. Electron microscopy confirmed VLP formation when MARV GP and matrix protein VP40 co-expressed. We vaccinated guinea pigs with a two-component mRNA vaccine encoding for GP and VP40 (VLP) or GP alone. At the highest dose, both vaccines protected fully, although the VLP vaccine elicited a slightly lower humoral response than the GP-only group. However, at low doses, GP-only mRNA conferred 100% protection, whereas the VLP exhibited only partial protection. In mice, VLP mRNA induced a moderate preference for GP-specific CD8+ T cells responses, whereas the GP-only mRNA somewhat favored CD4+ T cell responses. Guinea pig whole blood RNA-seq revealed that the VLP vaccine down-regulated genes associated with various biological and metabolic processes, including the NF-κB signaling pathway, whereas the GP-only vaccine upregulated interferon signaling. Overall, the VLP mRNA vaccine was less immunogenic and protective, whereas the GP-only mRNA vaccine conferred robust protection by as little as one µg dose in guinea pigs.
Authors
Chandru Subramani, Michelle N. Meyer, Matthew A. Hyde, Margaret E. Comeaux, Haiping Hao, James E. Crowe Jr., Vsevolod L. Popov, Harshwardhan Thaker, Sunny Himansu, Andrea Carfi, Alexander Bukreyev
Abstract
Bloodstream bacterial infections cause one-third of deaths from bacterial infections, and eradication of circulating bacteria is essential to prevent disseminated infections. We here found that hepcidin, the master regulator of systemic iron homeostasis, affected Kupffer cell (KC) immune defense against bloodstream bacterial infections by modulating the gut commensal bacteria-derived tryptophan derivative indole-3-propionic acid (IPA). Hepcidin deficiency impaired bacterial capture by KCs and exacerbated systemic bacterial dissemination through morphological changes in KCs. Gut microbiota depletion and fecal microbiota transplantation revealed that the gut microbiota mediated the alteration of KCs volume. Mechanistically, hepcidin deficiency led to a decreased abundance of the IPA-producing commensal Lactobacillus intestinalis and a concomitant reduction in the gut-to-liver shuttling of its metabolite IPA. IPA supplementation or Lactobacillus intestinalis colonization restored the KC volume and hepatic immune defense against bloodstream bacterial infection in hepcidin-deficient mice. Moreover, hepcidin levels in patients with bacteremia were associated with days of antibiotic usage and hospitalization. Collectively, our findings described a previously unappreciated role of hepcidin in sustaining KC-mediated hepatic defense against bloodstream bacterial infections through the gut commensal Lactobacillus intestinalis and its tryptophan derivative IPA. More importantly, restoring the crosstalk between the gut microbiota and liver through IPA-inspired therapies may offer a promising strategy for enhancing the host defense against bloodstream bacterial infections in those with low hepcidin levels and a high risk for bacterial infections.
Authors
Yihang Pan, Lihua Shen, Zehua Wu, Xueke Wang, Xiwang Liu, Yan Zhang, Qinyu Luo, Sijin Liu, Xiangming Fang, Qiang Shu, Qixing Chen
Abstract
Chagas disease, caused by Trypanosoma cruzi, is endemic to Latin America and is characterized by chronic inflammation of cardiac tissues due to parasite persistence. Hypoxia within infected tissues may trigger the stabilization of HIF-1 and be linked to ATP release. Extracellular ATP exhibits microbicidal effects but is scavenged by CD39 and CD73 ectonucleotidases, which ultimately generate adenosine (ADO), a potent immunosuppressor. Here, we comprehensively study the importance of HIF-1 stabilization and the CD39/CD73/ADO axis, on CD4+ T cells with the cytotoxic phenotype, in facilitating the persistence of T. cruzi. Myocardial infection induces prominent areas of hypoxia, which is concomitant with HIF-1α stabilization in T cells and linked to early expansion of CD39+CD73+CD4+ T cell infiltrating population. Functional assays further demonstrate that HIF-1 stabilization and CD73 activity are associated with impaired CD4+ T cell cytotoxic potential. RNA-Seq analysis reveals that HIF-1 and purinergic signaling pathways are overrepresented in cardiac tissues of patients with end-stage Chagas disease. The findings highlight a major effect of purinergic signaling on CD4+ T cells with potential cytotoxic capacity in the setting of T. cruzi infection and have translational implications for therapy.
Authors
Gastón Bergero, Yanina L. Mazzocco, Sebastian Del Rosso, Ruining Liu, Zoé M. Cejas Gallardo, Simon C. Robson, Martin Rottenberg, Maria P. Aoki
Abstract
BACKGROUND. Reversal reactions (RR) in leprosy are acute immune episodes marked by inflammation and bacterial clearance, offering a model to study the dynamics of host responses to Mycobacterium leprae. These episodes are often severe and difficult to treat, frequently progressing to permanent disabilities. We aimed to characterize the immune mechanisms and identify antimicrobial effectors during RR. METHODS. We performed RNA sequencing on paired skin biopsy specimens from nine leprosy patients collected before and at RR diagnosis, followed by differential gene expression and functional analysis. A machine learning classifier was applied to predict membrane-permeabilizing proteins. Antimicrobial activity was assessed in M. leprae-infected macrophages and axenic cultures. RESULTS. In the paired pre-RR and RR biopsy specimens, a 64-gene antimicrobial response signature was upregulated during RR and correlated with reduced M. leprae burden. Predicted upstream regulators included IL-1β, TNF, IFN-γ, and IL-17, indicating activation of both Th1 and Th17 pathways. A machine learning classifier identified 28 genes with predicted membrane-permeabilizing antimicrobial activity, including S100A8. Four proteins (S100A7, S100A8, CCL17, CCL19) demonstrated antimicrobial activity against M. leprae in vitro. Scanning electron microscopy revealed membrane damage in bacteria exposed to these proteins. CONCLUSION. RR is associated with a robust antimicrobial gene program regulated by Th1/Th17 cytokines. We identified potentially novel host antimicrobial effectors that exhibit activity against M. leprae, suggesting potential strategies to bolster Th1/Th17 responses for combating intracellular mycobacterial infections. FUNDING. NIH grants R01 AI022553, R01 AR040312, R01 AR073252, R01 AI166313, R01 AI169526, P50 AR080594, 4R37 AI052453-21, and NSF grant DMR2325840.
Authors
Priscila R. Andrade, Feiyang Ma, Jing Lu, Jaime de Anda, Ernest Y. Lee, George W. Agak, Craig J. Dobry, Bruno J. de Andrade Silva, Rosane M.B. Teles, Lilah A. Mansky, Jonathan Perrie, Dennis J. Montoya, Bryan D. Bryson, Johann E. Gudjonsson, Gerard C.L. Wong, Euzenir N. Sarno, Matteo Pellegrini, Robert L. Modlin
Abstract
Influenza-associated bacterial super-infections in the lung lead to increased morbidity and mortality. Nearly all people have pre-existing memory to influenza virus, which can protect against subsequent infection in the lung. This study explored the role B cells play in protection against bacterial (Staphylococcus aureus or Klebsiella pneumoniae) super-infection with previous heterotypic influenza memory. B cell deficiency resulted in an increased inflammatory lung environment and lung tissue injury during super-infection. Loss of B cells increased populations of memory CD8+ T cells in the lung and these CD8+ T cells were transcriptionally and functionally distinct from WT mice. Use of antibody-deficient mouse models showed that this phenotype was specifically due to loss of antibody production from B cells. Passive immunization with influenza-antibody serum in B cell deficient mice rescued the CD8+ T cell phenotype. CD8+ T cell depletion and lethal super-infection challenge experiments showed that the cytotoxic memory CD8+ T cells from B cell deficient mice protect against super-infection bacterial burden and mortality. These findings provide insight into the importance of B cells for regulating immune responses against infection.
Authors
Leigh M. Miller, Alexis M. Duray, Ellyse M. Cipolla, Flavia Rago, Brooke P. Dresden, Kristen L. Parenteau, Abhigya Gupta, John F. Alcorn
Abstract
Enterovirus D68 (EV-D68) is associated with acute flaccid myelitis (AFM), a poliomyelitis-like illness causing paralysis in young children. However, mechanisms of paralysis are unclear, and antiviral therapies are lacking. To better understand EV-D68 disease, we inoculated newborn mice intracranially to assess viral tropism, virulence, and immune responses. Wild-type (WT) mice inoculated intracranially with a neurovirulent strain of EV-D68 showed infection of spinal cord neurons and developed paralysis. Spinal tissue from infected mice revealed increased chemokines, inflammatory monocytes, macrophages, and T cells relative to controls, suggesting that immune cell infiltration influences pathogenesis. To define the contribution of cytokine-mediated immune cell recruitment to disease, we inoculated mice lacking CCR2, a receptor for several EV-D68-upregulated cytokines, or RAG1, which is required for lymphocyte maturation. WT, Ccr2-/-, and Rag1-/- mice had comparable viral titers in spinal tissue. However, Ccr2-/- and Rag1-/- mice were significantly less likely to be paralyzed relative to WT mice. Consistent with impaired T cell recruitment to sites of infection in Ccr2-/- and Rag1 -/- mice, antibody-mediated depletion of CD4+ or CD8+ T cells from WT mice diminished paralysis. These results indicate that immune cell recruitment to the spinal cord promotes EV-D68-associated paralysis and illuminate new targets for therapeutic intervention.
Authors
Mikal A. Woods Acevedo, Jie Lan, Sarah Maya, Jennifer E. Jones, Isabella E. Bosco, John V. Williams, Megan C. Freeman, Terence S. Dermody
Abstract
Air pollution is a serious environmental threat to public health; however, the molecular basis underlying its detrimental effects on respiratory fitness remains poorly understood. Here, we show that exposure to particulate matter ≤2.5 µm (PM2.5), a significant fraction of air pollutants, induces the generation of reactive aldehyde species in the airway. We identified aldehyde dehydrogenase 1A1 (ALDH1A1), which is selectively expressed in airway epithelium, as an enzyme responsible for detoxifying these reactive aldehyde species. Loss of ALDH1A1 function results in the accumulation of aldehyde adducts in the airway, which selectively impairs mucociliary clearance (MCC), a critical defense mechanism against respiratory pathogens. Thus, ALDH1A1-deficient mice pre-exposed to PM2.5 exhibited increased susceptibility to pneumonia. Conversely, pharmacological enhancement of ALDH1A1 activity promoted the restoration of MCC function. These findings elucidate the critical role of aldehyde metabolism in protecting against PM2.5 exposure, offering a potential target to mitigate the negative health consequences of air pollution.
Authors
Noriko Shinjyo, Haruna Kimura, Tomomi Yoshihara, Jun Suzuki, Masaya Yamaguchi, Shigetada Kawabata, Yasutaka Okabe
Abstract
Immune and clinical outcomes to Mycobacterium tuberculosis (Mtb) infection vary greatly between individuals yet the underlying genetic and cellular mechanisms driving this heterogeneity remain poorly understood. We performed a cellular genome-wide association study (GWAS) to identify genetic variants associated with Mtb-induced monocyte transcriptional expression of IL1B, IL6, TNF, and IFNB1 via RNA-seq in a Ugandan cohort. Significantly associated variants were assessed for transferability in an independent Seattle cohort, further validated in vitro, and assessed for clinical phenotype associations. We identified 77 loci suggestively associated with Mtb-induced cytokine expression in monocytes in Uganda. SNPs associated with Mtb-induced TNF were enriched within alpha-linolenic acid metabolism pathway genes which was validated in vitro using PLA2 inhibitors. Four loci maintained significant associations in Seattle. We validated cytokine effect with siRNA knockdown for two of these loci which mapped to the genes SLIT3 and SLC1A1. Furthermore, exogenous treatment of macrophages with SLIT3 enhanced Mtb intracellular replication. Finally, SLC1A1 and SLIT3 variants were associated with susceptibility to tuberculous meningitis (TBM) and subsequent survival in a Vietnamese cohort, respectively. In sum, we identified multiple variants and pathways associated with Mtb-induced cytokine transcriptional responses that validated in vitro and were associated with clinical TB susceptibility.
Authors
Joshua J. Ivie, Kimberly A. Dill-McFarland, Jason D. Simmons, Glenna J. Peterson, Penelope H. Benchek, Harriet Mayanja-Kizza, Lily E. Veith, Moeko Agata, Dang T.M. Ha, Ho D.T. Nghia, W. Henry Boom, Catherine M. Stein, Chiea C. Khor, Guy E. Thwaites, Hoang T. Hai, Nguyen T.T. Thuong, Xuling Chang, Sarah J. Dunstan, Thomas R. Hawn
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