Infectious disease
Abstract
Despite the discovery of key pattern recognition receptors and CD4+ T cell subsets in laboratory mice, there is ongoing discussion of the value of murine models to reflect human disease. Pneumocystis is an AIDS-defining illness, in which risk of infection is inversely correlated with peripheral CD4+ T cell counts. Due to medical advances in the control of HIV, the current epidemiology of Pneumocystis infection is predominantly due to primary human immunodeficiencies and immunosuppressive therapies. To this end, we found that every human genetic immunodeficiency associated with Pneumocystis infection that has been tested in mice recapitulated susceptibility. For example, humans with a loss-of-function IL21R mutation are severely immunocompromised. We found that IL-21R, in addition to CD4+ T cell intrinsic STAT3 signaling, were required for generating protective antifungal class-switched antibody responses, as well as effector T cell–mediated protection. Furthermore, CD4+ T cell intrinsic IL-21R/STAT3 signaling was required for CD4+ T cell effector responses, including IL-22 production. Recombinant IL-22 administration to Il21r–/– mice induced the expression of a fungicidal peptide, cathelicidin antimicrobial peptide, which showed in vitro fungicidal activity. In conclusion, SPF laboratory mice faithfully replicate many aspects of human primary immunodeficiency and provide useful tools to understand the generation and nature of effector CD4+ T cell immunity.
Authors
Waleed Elsegeiny, Mingquan Zheng, Taylor Eddens, Richard L. Gallo, Guixiang Dai, Giraldina Trevejo-Nunez, Patricia Castillo, Kara Kracinovsky, Hillary Cleveland, William Horne, Jonathan Franks, Derek Pociask, Mark Pilarski, John F. Alcorn, Kong Chen, Jay K. Kolls
Abstract
Kidney injury is a frequent outcome in patients with disseminated Candida albicans fungal infections. IL-17 receptor (IL-17R) signaling is critical for renal protection against disseminated candidiasis, but the identity and function of IL-17–responsive cells in mediating renal defense remains an active area of debate. Using BM chimeras, we found that IL-17R signaling is required only in nonhematopoietic cells for immunity to systemic C. albicans infection. Since renal tubular epithelial cells (RTEC) are highly responsive to IL-17 in vitro, we hypothesized that RTEC might be the dominant target of IL-17 activity in the infected kidney. We generated mice with a conditional deletion of IL-17 receptor A (Il17ra) in RTEC (Il17raΔRTEC). Strikingly, Il17raΔRTEC mice showed enhanced kidney damage and early mortality following systemic infection, very similar to Il17ra–/– animals. Increased susceptibility to candidiasis in Il17raΔRTEC mice was associated with diminished activation of the renal protective Kallikrein-kinin system (KKS), resulting in reduced apoptosis of kidney-resident cells during hyphal invasion. Moreover, protection was restored by treatment with bradykinin, the major end-product of KKS activation, which was mediated dominantly via bradykinin receptor b1. These data show that IL-17R signaling in RTEC is necessary and likely sufficient for IL-17–mediated renal defense against fatal systemic C. albicans infection.
Authors
Kritika Ramani, Chetan V. Jawale, Akash H. Verma, Bianca M. Coleman, Jay K. Kolls, Partha S. Biswas
Abstract
Using a mouse retroviral model, we have shown that mAb-based immunotherapy can induce life-long endogenous protective immunity (vaccine-like effects). This observation has potentially important consequences for treating life-threatening human viral infections. Here, we investigated the role of neutrophils in this effect. Neutrophils are innate immunity effector cells with well-established microbe-killing activities that are rapidly mobilized upon infection. They are also emerging as orchestrators of innate and adaptive immunities. However, their immunomodulatory activity during antiviral mAb immunotherapies has never been studied. Our data reveal that neutrophils have an essential role in immunotherapy-induced immune protection of infected mice. Unexpectedly, neutrophils have a limited effect in controlling viral propagation upon passive immunotherapy administration, which is mostly mediated by NK cells. Instead, neutrophils operate as essential inducers of a potent host humoral antiviral response. Thus, neutrophils play an unexpected key role in protective immunity induction by antiviral mAbs. Our work opens approaches to improve antiviral immunotherapies, as it suggests that preserving neutrophil functions and counts might be required for achieving mAb-induced protective immunity.
Authors
Mar Naranjo-Gomez, Jennifer Lambour, Marc Piechaczyk, Mireia Pelegrin
Abstract
Malaria remains one of the world’s most significant human infectious diseases and cerebral malaria (CM) is its most deadly complication. CM pathogenesis remains incompletely understood, hindering the development of therapeutics to prevent this lethal complication. Elevated levels of the chemokine CXCL10 are a biomarker for CM, and CXCL10 and its receptor CXCR3 are required for experimental CM (ECM) in mice, but their role has remained unclear. Using multiphoton intravital microscopy, CXCR3 receptor– and ligand–deficient mice and bone marrow chimeric mice, we demonstrate a key role for endothelial cell–produced CXCL10 in inducing the firm adhesion of T cells and preventing their cell detachment from the brain vasculature. Using a CXCL9 and CXCL10 dual-CXCR3-ligand reporter mouse, we found that CXCL10 was strongly induced in the brain endothelium as early as 4 days after infection, while CXCL9 and CXCL10 expression was found in inflammatory monocytes and monocyte-derived DCs within the blood vasculature on day 8. The induction of both CXCL9 and CXCL10 was completely dependent on IFN-γ receptor signaling. These data demonstrate that IFN-γ–induced, endothelium-derived CXCL10 plays a critical role in mediating the T cell–endothelial cell adhesive events that initiate the inflammatory cascade that injures the endothelium and induces the development of ECM.
Authors
Elizabeth W. Sorensen, Jeffrey Lian, Aleksandra J. Ozga, Yoshishige Miyabe, Sophina W. Ji, Shannon K. Bromley, Thorsten R. Mempel, Andrew D. Luster
Abstract
Replication competent HIV-1 persists in a subpopulation of CD4+ T lymphocytes despite prolonged antiretroviral treatment. This residual reservoir of infected cells harbors transcriptionally silent provirus capable of reigniting productive infection upon discontinuation of antiretroviral therapy. Certain classes of drugs can activate latent virus but not at levels that lead to reductions in HIV-1 reservoir size in vivo. Here, we show the utility of CD4+ receptor targeting exosomes as an HIV-1 latency reversal agent (LRA). We engineered human cellular exosomes to express HIV-1 Tat, a protein that is a potent transactivator of viral transcription. Preparations of exosomal Tat-activated HIV-1 in primary, resting CD4+ T lymphocytes isolated from antiretroviral-treated individuals with prolonged periods of viral suppression and led to the production of replication competent HIV-1. Furthermore, exosomal Tat increased the potency of selected LRA by over 30-fold in terms of HIV-1 mRNA expression, thereby establishing it as a potentially new class of biologic product with possible combinatorial utility in targeting latent HIV-1.
Authors
Xiaoli Tang, Huafei Lu, Mark Dooner, Stacey Chapman, Peter J. Quesenberry, Bharat Ramratnam
Abstract
Several reports have demonstrated that mouse Cx3cr1 signaling promotes monocyte/macrophage survival. In agreement, we previously found that, in a mouse model of systemic candidiasis, genetic deficiency of Cx3cr1 resulted in increased mortality and impaired tissue fungal clearance associated with decreased macrophage survival. We translated this finding by showing that the dysfunctional CX3CR1 variant CX3CR1-M280 was associated with increased risk and worse outcome of human systemic candidiasis. However, the impact of this mutation on human monocyte/macrophage survival is poorly understood. Herein, we hypothesized that CX3CR1-M280 impairs human monocyte survival. We identified WT (CX3CR1-WT/WT), CX3CR1-WT/M280 heterozygous, and CX3CR1-M280/M280 homozygous healthy donors of European descent, and we show that CX3CL1 rescues serum starvation–induced cell death in CX3CR1-WT/WT and CX3CR1-WT/M280 but not in CX3CR1-M280/M280 monocytes. CX3CL1-induced survival of CX3CR1-WT/WT monocytes is mediated via AKT and ERK activation, which are both impaired in CX3CR1-M280/M280 monocytes, associated with decreased blood monocyte counts in CX3CR1-M280/M280 donors at steady state. Instead, CX3CR1-M280/M280 does not affect monocyte CX3CR1 surface expression or innate immune effector functions. Together, we show that homozygocity of the M280 polymorphism in CX3CR1 is a potentially novel population-based genetic factor that influences human monocyte signaling.
Authors
Amanda L. Collar, Muthulekha Swamydas, Morgan O’Hayre, Md Sanaullah Sajib, Kevin W. Hoffman, Satya P. Singh, Ahmad Mourad, Melissa D. Johnson, Elise M.N. Ferre, Joshua M. Farber, Jean K. Lim, Constantinos M. Mikelis, J. Silvio Gutkind, Michail S. Lionakis
Abstract
Despite the fact that many therapeutic strategies have been adopted to delay the development of sepsis, sepsis remains one of the leading causes of death in noncoronary intensive care units. Recently, sepsis-3 was defined as life-threatening organ dysfunction due to a dysregulated host response to infection. Here, we report that swiprosin-1 (also known as EFhd2) plays an important role in the macrophage immune response to LPS-induced or cecal ligation and puncture–induced (CLP-induced) sepsis in mice. Swiprosin-1 depletion causes higher mortality, more severe organ dysfunction, restrained macrophage recruitment in the lung and kidney, and attenuated inflammatory cytokine production (including IL-1β, IL-6, TNF-α, IL-10, and IFN-γ). The immunosuppression caused by swiprosin-1 deficiency is manifested by impaired bactericidal capacity and decreased HLA-DR expression in macrophages. Swiprosin-1 affects the activation of the JAK2/STAT1/STAT3 pathway by regulating the expression of IFN-γ receptors in macrophages. Our findings provide a potential target for the regulation of the macrophage immune response in sepsis.
Authors
Su Zhang, Ye Tu, Yi-Ming Sun, Ya Li, Rong-Mei Wang, Yongbing Cao, Ling Li, Li-Chao Zhang, Zhi-Bin Wang
Abstract
Sensing of pathogens by host pattern recognition receptors is essential for activating the immune response during infection. We used a nonlethal murine model of malaria (Plasmodium yoelii 17XNL) to assess the contribution of the pattern recognition receptor cyclic GMP-AMP synthase (cGAS) to the development of humoral immunity. Despite previous reports suggesting a critical, intrinsic role for cGAS in early B cell responses, cGAS-deficient (cGAS–/–) mice had no defect in the early expansion or differentiation of Plasmodium-specific B cells. As the infection proceeded, however, cGAS–/– mice exhibited higher parasite burdens and aberrant germinal center and memory B cell formation when compared with littermate controls. Antimalarial drugs were used to further demonstrate that the disrupted humoral response was not B cell intrinsic but instead was a secondary effect of a loss of parasite control. These findings therefore demonstrate that cGAS-mediated innate-sensing contributes to parasite control but is not intrinsically required for the development of humoral immunity. Our findings highlight the need to consider the indirect effects of pathogen burden in investigations examining how the innate immune system affects the adaptive immune response.
Authors
William O. Hahn, Noah S. Butler, Scott E. Lindner, Holly M. Akilesh, D. Noah Sather, Stefan H.I. Kappe, Jessica A. Hamerman, Michael Gale Jr., W. Conrad Liles, Marion Pepper
Abstract
Malaria eradication necessitates new tools to fight the evolving and complex Plasmodium pathogens. These tools include prophylactic drugs that eliminate Plasmodium liver stages and consequently prevent clinical disease, decrease transmission, and reduce the propensity for resistance development. Currently, the identification of these drugs relies on in vitro P. falciparum liver stage assays or in vivo causal prophylaxis assays using rodent malaria parasites; there is no method to directly test in vivo liver stage activity of candidate antimalarials against the human malaria–causing parasite P. falciparum. Here, we use a liver-chimeric humanized mouse (FRG huHep) to demonstrate in vivo P. falciparum liver stage development and describe the efficacy of clinically used and candidate antimalarials with prophylactic activity. We show that daily administration of atovaquone-proguanil (ATQ-PG; ATQ, 30 mg/kg, and PG, 10 mg/kg) protects 5 of 5 mice from liver stage infection, consistent with the use in humans as a causal prophylactic drug. Single-dose primaquine (60 mg/kg) has similar activity to that observed in humans, demonstrating the activity of this drug (and its active metabolites) in FRG huHep mice. We also show that DSM265, a selective Plasmodial dihydroorotate dehydrogenase inhibitor with causal prophylactic activity in humans, reduces liver stage burden in FRG huHep mice. Finally, we measured liver stage–to–blood stage transition of the parasite, the ultimate readout of prophylactic activity and measurement of infective capacity of parasites in the liver, to show that ATQ-PG reduces blood stage patency to below the limit of quantitation by quantitative PCR (qPCR). The FRG huHep model, thus, provides a platform for preclinical evaluation of drug candidates for liver stage causal prophylactic activity, pharmacokinetic/pharmacodynamics studies, and biological studies to investigate the mechanism of action of liver stage active antimalarials.
Authors
Erika L. Flannery, Lander Foquet, Vorada Chuenchob, Matthew Fishbaugher, Zachary Billman, Mary Jane Navarro, William Betz, Tayla M. Olsen, Joshua Lee, Nelly Camargo, Thao Nguyen, Carola Schafer, Brandon K. Sack, Elizabeth M. Wilson, Jessica Saunders, John Bial, Brice Campo, Susan A. Charman, Sean C. Murphy, Margaret A. Phillips, Stefan H.I. Kappe, Sebastian A. Mikolajczak
Abstract
Declining levels of maternal antibodies were shown to sensitize infants born to dengue-immune mothers to severe disease during primary infection, through the process of antibody-dependent enhancement of infection (ADE). With the recent approval for human use of Sanofi-Pasteur’s chimeric dengue vaccine CYD-TDV and several vaccine candidates in clinical development, the scenario of infants born to vaccinated mothers has become a reality. This raises 2 questions: will declining levels of maternal vaccine-induced antibodies cause ADE; and, will maternal antibodies interfere with vaccination efficacy in the infant? To address these questions, the above scenario was modeled in mice. Type I IFN–deficient female mice were immunized with live attenuated DENV2 PDK53, the core component of the tetravalent DENVax candidate currently under clinical development. Pups born to PDK53-immunized dams acquired maternal antibodies that strongly neutralized parental strain 16681, but not the heterologous DENV2 strain D2Y98P-PP1, and instead caused ADE during primary infection with this strain. Furthermore, pups failed to seroconvert after PDK53 vaccination, owing to maternal antibody interference. However, a cross-protective multifunctional CD8+ T cell response did develop. Thus, our work advocates for the development of dengue vaccine candidates that induce protective CD8+ T cells despite the presence of enhancing, interfering maternal antibodies.
Authors
Jian Hang Lam, Yen Leong Chua, Pei Xuan Lee, Julia María Martínez Gómez, Eng Eong Ooi, Sylvie Alonso
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