Infectious disease
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
Abstract
Human cutaneous leishmaniasis (CL) is characterized by chronic skin pathology. Experimental and clinical data suggest that immune checkpoints (ICs) play a crucial role in disease outcome, but the cellular and molecular niches that facilitate IC molecule expression during leishmaniasis are ill defined. In Sri Lankan patients with CL, indoleamine 2,3-dioxygenase 1 (IDO1) and programmed death–ligand 1 (PD-L1) were enriched in skin lesions, and reduced PD-L1 expression early after treatment initiation was predictive of a cure rate following antimonial therapy. Here, we used spatial cell interaction mapping to identify IL-32–expressing CD8+ memory T cells and Tregs as key components of the IDO1/PD-L1 niche in Sri Lankan patients with CL and in patients with distinct forms of dermal leishmaniasis in Brazil and India. Furthermore, the abundance of IL-32+ cells and IL-32+CD8+ T cells at treatment initiation was negatively correlated with the rate of cure in Sri Lankan patients. This study provides insights into the spatial mechanisms underpinning IC expression during CL and offers a strategy for identifying additional biomarkers of treatment response.
Authors
Nidhi S. Dey, Shoumit Dey, Naj Brown, Sujai Senarathne, Luiza Campos Reis, Ritika Sengupta, Jose A.L. Lindoso, Sally R. James, Lesley Gilbert, Dave Boucher, Mitali Chatterjee, Hiro Goto, Shalindra Ranasinghe, Paul M. Kaye
Abstract
We leveraged specimens from the RV217 prospective study that enrolled participants at high risk of HIV-1 acquisition to investigate how NK, conventional T cells, and unconventional T cells influence HIV-1 acquisition. We observed low levels of α4β7 expression on memory CD4 T cells and iNKT cells, two cell types highly susceptible to HIV-1 infection, in highly exposed seronegative (HESN) compared to highly exposed seroconverter (HESC) participants. NK cells from HESN had higher levels of α4β7 compared to HESC, presented a quiescent phenotype, and had a higher capacity to respond to opsonized target cells. We also measured translocated microbial products in plasma and found differences in phylum distribution between HESN and HESC that were associated with the immune phenotypes impacting the risk of HIV-1 acquisition. Finally, a logistic regression model combining features of NK cells activation, α4β7 expression on memory CD4 T cells, and Tbet expression by iNKT cells achieved the highest accuracy in identifying HESN and HESC participants. This immune signature comprised of increased α4β7 on cells susceptible to HIV infection combined with higher NK cells activation and lower gut homing potential could impact the efficacy of HIV-1 prevention strategies such as vaccines.
Authors
Kawthar Machmach, Kombo F. N'guessan, Rohit Farmer, Sucheta Godbole, Dohoon Kim, Lauren McCormick, Noemia S. Lima, Amy R. Henry, Farida Laboune, Isabella Swafford, Sydney K. Mika, Bonnie M. Slike, Jeffrey R. Currier, Leigh Anne Eller, Julie A. Ake, Sandhya Vasan, Merlin L. Robb, Shelly J. Krebs, Daniel C. Douek, Dominic Paquin-Proulx
Abstract
Authors
Tran Xuan Ngoc Huy, Huynh Tan Hop
Abstract
The rapid viral rebound observed following treatment interruption, despite prolonged time on antiretroviral therapy with plasma HIV-RNA levels <40 copies/mL, suggests persistent HIV-1 reservoir(s) outside of the blood. Studies of HIV-1 proviruses in autopsy tissue samples have hinted at their persistence. However, their distribution across different anatomical compartments and their transcriptional activity within tissues remains unclear. The present study has examined molecular DNA and RNA reservoirs of HIV-1 in autopsy samples from 13 individuals with HIV-1 infection. Of the 13, 5 had detectable levels of HIV-1 RNA in plasma while 8 did not. Cell associated HIV-RNA was detected in 12 out of 13 donors and in 27 of the 30 different tissues examined. HIV-specific DNA and RNA were widely distributed and predominantly associated with clonal expansions. No significant differences were noted between the groups and no tissues were preferentially affected. These data imply that a substantial seeding of tissues with cells harboring transcriptionally active proviral DNA can be seen in the setting of HIV-1 infection despite ART and highlight one of the challenges in achieving an HIV-1 cure.
Authors
Hiromi Imamichi, Ven Natarajan, Francesca Scrimieri, Mindy Smith, Yunden Badralmaa, Marjorie Bosche, Jack M. Hensien, Thomas Buerkert, Weizhong Chang, Brad T. Sherman, Kanal Singh, H. Clifford Lane
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ISSN: 0021-9738 (print), 1558-8238 (online)