Infectious disease
Abstract
The ACTH test diagnoses relative adrenal insufficiency (RAI) or critical illness-related corticosteroid insufficiency (CIRCI). Initially, guidelines recommended corticosteroid/glucocorticoid (GC) therapy for septic patients with RAI, but later trials did not show a survival benefit, leading to updated guidelines that abandon targeting RAI or CIRCI. Recent studies with an RAI mouse model showed a clear survival benefit from GC therapy in mice with RAI, suggesting that inconclusive GC clinical trials might be due to issues with the ACTH test rather than targeting RAI. To investigate, we performed the ACTH test in septic mice. Interestingly, the ACTH test identified most mice as having adrenal insufficiency in early and middle stages of sepsis, even those with a normal adrenal stress response. Surprisingly, the ACTH test increased inflammatory cytokine to lethal levels, moderately increasing mortality in septic mice. This study revealed significant flaws in the ACTH test for diagnosing RAI/CIRCI. It not only fails to correctly identify these conditions, leading to misguided use of GC, but also induces a lethal inflammatory response in sepsis. These findings suggest that inconclusive GC therapy trials may be due to the problematic nature of the ACTH test rather than ineffectiveness of targeting RAI/CIRCI.
Authors
Dan Hao, Qian Wang, Misa Ito, Jianyao Xue, Ling Guo, Bin Huang, Chieko Mineo, Philip W. Shaul, Xiang-An Li
Abstract
Chlamydia trachomatis (CT) is the most common bacterial sexually transmitted infection globally. Understanding natural immunity to CT will inform vaccine design. This study aimed to profile immune cells and associated functional features in CT-infected women, and determine immune profiles associated with reduced risk of ascended endometrial CT infection and CT reinfection. PBMCs from CT-exposed women were profiled by mass cytometry and random forest models identified key features that distinguish outcomes. CT+ participants exhibited higher frequencies of CD4+ Th2, Th17, and Th17 DN CD4 T effector memory (TEM) cells than uninfected participants with decreased expression of T cell activation and differentiation markers. Minimal differences were detected between women with or without endometrial CT infection. Participants who remained follow-up negative (FU-) showed higher frequencies of CD4 T central memory (TCM) Th1, Th17, Th1/17, and Th17 DN but reduced CD4 TEM Th2 cells than FU+ participants. Expression of markers associated with central memory and Th17 lineage were increased on T cell subsets among FU- participants. These data indicate that peripheral T cells exhibit distinct features associated with resistance to CT reinfection. The highly plastic Th17 lineage appears to contribute to protection. Addressing these immune nuances could promote efficacy of CT vaccines.
Authors
Kacy S. Yount, Chi-Jane Chen, Avinash Kollipara, Chuwen Liu, Neha Vivek Mokashi, Xiaojing Zheng, C Bruce Bagwell, Taylor B. Poston, Harold C. Wiesenfeld, Sharon L. Hillier, Catherine M. O'Connell, Natalie Stanley, Toni Darville
Abstract
Dengue is widespread in tropical and subtropical regions globally and imposes a considerable disease burden. Annually, dengue virus (DENV) causes up to 400 million infections, of which approximately 25% present with clinical manifestations ranging from mild to fatal. Despite its significance as a growing public health concern, developing effective DENV vaccines has been challenging. One reason is the lack of comprehensive understanding of the influence exerted by prior DENV infections and immune responses with cross-reactive properties. To investigate this, we collected samples from a pediatric cohort study in dengue-endemic Managua, Nicaragua. We characterized T cell responses in 71 healthy children who had previously experienced 1 or more natural DENV infections and who, within 1 year after sample collection, had a subsequent DENV infection that was either symptomatic or inapparent. Our study investigated the effect of preexisting DENV-specific T cell responses on clinical outcomes of subsequent DENV infection. We assessed DENV-specific T cell responses using an activation-induced marker assay. Children with only 1 prior DENV infection displayed heterogeneous DENV-specific CD4+ and CD8+ T cell frequencies. In contrast, children with 2 or more prior DENV infections showed significantly higher DENV-specific CD4+ and CD8+ T cell frequencies associated with inapparent rather than symptomatic outcomes in subsequent infection. These findings demonstrate the protective role of DENV-specific T cells against symptomatic DENV infection and advance efforts to identify protective immune correlates against dengue.
Authors
Rosa Isela Gálvez, Amparo Martínez-Pérez, E. Alexandar Escarrega, Tulika Singh, José Victor Zambrana, Ángel Balmaseda, Eva Harris, Daniela Weiskopf
Abstract
Access to the brain for treating neurological sequalae requires a craniotomy, which can be complicated by infection. Staphylococcus aureus accounts for half of craniotomy infections, increasing morbidity in a medically fragile patient population. T cells preferentially traffic to the brain during craniotomy infection; however, their functional importance is unknown. Using a mouse model of S. aureus craniotomy infection, CD4+ T cells were critical for bacterial containment, as treatment of WT animals with anti-CD4 exacerbated infection that was similar to phenotypes in Rag1–/– mice. Single-cell RNA-Seq (scRNA-Seq) revealed transcriptional heterogeneity in brain CD3+ infiltrates, with CD4+ cells most prominent that displayed Th1- and Th17-like characteristics, and adoptive transfer of either subset in Rag1–/– animals during early infection prevented S. aureus outgrowth. scRNA-Seq identified a robust IFN signature in several innate immune clusters, and examination of cell-to-cell interactions revealed extensive T cell crosstalk with monocytes/macrophages that was also observed in human craniotomy infection. A cooperative role for Th1 and Th17 responses was demonstrated by treatment of Ifng–/– mice with IL-17A neutralizing antibody that recapitulated phenotypes in Rag1–/– animals. Collectively, these findings implicate Th1- and Th17-mediated proinflammatory responses in shaping the innate immune landscape for S. aureus containment during craniotomy infection.
Authors
Gunjan Kak, Zachary Van Roy, Rachel W. Fallet, Lee E. Korshoj, Tammy Kielian
Abstract
Endothelial injury destroys endothelial barrier integrity, triggering organ dysfunction and ultimately resulting in sepsis-related death. Considerable attention has been focused on identifying effective targets for inhibiting damage to endothelial cells to treat endotoxemia-induced septic shock. Global gasdermin D (Gsdmd) deletion reportedly prevents death caused by endotoxemia. However, the role of endothelial GSDMD in endothelial injury and lethality in lipopolysaccharide-induced (LPS-induced) endotoxemia and the underlying regulatory mechanisms are unknown. Here, we show that LPS increases endothelial GSDMD level in aortas and lung microvessels. We demonstrated that endothelial Gsdmd deficiency, but not myeloid cell Gsdmd deletion, protects against endothelial injury and death in mice with endotoxemia or sepsis. In vivo experiments suggested that hepatocyte GSDMD mediated the release of high-mobility group box 1, which subsequently binds to the receptor for advanced glycation end products in endothelial cells to cause systemic vascular injury, ultimately resulting in acute lung injury and lethality in shock driven by endotoxemia or sepsis. Additionally, inhibiting endothelial GSDMD activation via a polypeptide inhibitor alleviated endothelial damage and improved survival in a mouse model of endotoxemia or sepsis. These data suggest that endothelial GSDMD is a viable pharmaceutical target for treating endotoxemia and endotoxemia-induced sepsis.
Authors
Enyong Su, Xiaoyue Song, Lili Wei, Junqiang Xue, Xuelin Cheng, Shiyao Xie, Hong Jiang, Ming Liu
Abstract
BACKGROUND. Lymphopenia and failure of lymphocytes to mount an early IFN-γ response correlate with increased mortality in COVID-19. Given the essential role of CD4 helper and CD8 cytotoxic cells in eliminating viral pathogens, this profound loss in lymphocytes may impair patients’ ability to eliminate the virus. IL-7 is a pleiotropic cytokine that is obligatory for lymphocyte survival and optimal function. METHODS. We conducted a prospective, double-blind, randomized, placebo-controlled trial of CYT107, recombinant human IL-7, in 109 critically-ill lymphopenic COVID-19 patients. The primary endpoint was to assess CYT107’s effect on lymphocyte recovery with secondary clinical endpoints including safety, ICU and hospital length-of-stay, incidence of secondary infections, and mortality. RESULTS. CYT107 was well-tolerated without precipitating a cytokine storm or worsening pulmonary function. Absolute lymphocyte counts increased in both groups without significant difference between CYT107 and placebo. COVID-19 patients receiving CYT107 but not concomitant antiviral medications, known inducers of lymphopenia, had a final lymphocyte count that was 43% greater than placebo (p=0.067). There were significantly fewer treatment-emergent adverse events in CYT107 versus placebo-treated patients (p<0.001), consistent with a beneficial drug effect. Importantly, CYT107 treated patients had 44% fewer hospital-acquired infections versus placebo-treated patients (p=0.014). CONCLUSIONS. Given that hospital-acquired infections are responsible for a large percentage of COVID-19 deaths, this effect of CYT107 to decrease nosocomial infections could substantially reduce late morbidity and mortality in this highly lethal disease. The strong safety profile of CYT107 and its excellent tolerability provide support for trials of CYT107 in other potential pandemic respiratory viral infections. TRIAL REGISTRATION. NCT04379076, NCT04426201, NCT04442178, NCT04407689; NCT04927169
Authors
Manu Shankar-Hari, Bruno Francois, Kenneth E. Remy, Cristina Gutierrez, Stephen Pastores, Thomas Daix, Robin Jeannet, Jane Blood, Andrew H. Walton, Reinaldo Salomao, Georg Auzinger, David Striker, Robert S. Martin, Nitin J. Anand, James Bosanquet, Teresa Blood, Scott Brakenridge, Lyle L. Moldawer, Vidula Vachharajani, Cassian Yee, Felipe Dal-Pizzol, Michel Morre, Frederique Berbille, Marcel van den Brink, Richard Hotchkiss
Abstract
Chagas disease is a neglected tropical disease caused by Trypanosoma cruzi with clinical presentations ranging from asymptomatic to cardiac and/or gastrointestinal complications. The mechanisms of pathogenesis are still poorly understood, but T. cruzi strain diversity may be associated with disease progression. Therefore, we evaluated the transcriptomic response of PBMCs from macaques with natural chronic infections and tested for heterogeneity in their gene signatures. Remarkably, transcriptomic response to T. cruzi infection matched parasite strain profiles, indicating that parasite diversity is a key determinant of host response. While differences in adaptive immune responses were identified, more striking alterations of innate immune processes were detected. Thus, initial innate response to T. cruzi infection may be conditioned by parasite strain diversity, resulting in different profiles of trained immunity modulating subsequent adaptive responses, allowing parasite control or its persistence during the chronic phase. These results call for further characterization of the cross-talk between innate and adaptive immunity according to parasite diversity, and how altered trained immunity contributes to pathogenesis, as this may lead to better treatments and vaccines.
Authors
Hans Desale, Weihong Tu, Kelly Goff, Preston A. Marx, Claudia Herrera, Eric Dumonteil
Abstract
T cells are involved in protective immunity against numerous viral infections. Data regarding functional roles of human T cells in SARS-CoV-2 (SARS2) viral clearance in primary COVID-19 are limited. To address this knowledge gap, we assessed samples for associations between SARS2 upper respiratory tract viral RNA levels and early virus-specific adaptive immune responses for 95 unvaccinated clinical trial participants with acute primary COVID-19 aged 18–86 years old, approximately half of whom were considered at high risk for progression to severe COVID-19. Functionality and magnitude of acute SARS2-specific CD4+ and CD8+ T cell responses were evaluated, in addition to antibody responses. Most individuals with acute COVID-19 developed SARS2-specific T cell responses within 6 days of COVID-19 symptom onset. Early CD4+ T cell and CD8+ T cell responses were polyfunctional, and both strongly associated with reduced upper respiratory tract SARS2 viral RNA, independent of neutralizing antibody titers. Overall, these findings provide evidence for protective roles for circulating SARS2-specific CD4+ and CD8+ T cells during acute COVID-19.
Authors
Sydney I. Ramirez, Paul G. Lopez, Farhoud Faraji, Urvi M. Parikh, Amy Heaps, Justin Ritz, Carlee Moser, Joseph J. Eron, David Wohl, Judith Currier, Eric S. Daar, Alex Greninger, Paul Klekotka, Alba Grifoni, Daniela Weiskopf, Alessandro Sette, Bjoern Peters, Michael D. Hughes, Kara W. Chew, Davey M. Smith, Shane Crotty, for the Accelerating COVID-19 Therapeutic Interventions and Vaccines-2 (ACTIV-2)/A5401 Study Team
Abstract
Peptidoglycans (PGNs) are structural polymers of the bacterial cell wall and a common microbial molecular pattern encountered by our immune system daily. Low levels of PGNs are constitutively present in the systemic circulation in humans and elevate during inflammatory pathologies. Since all known PGN sensors are intracellular, PGN internalization is a prerequisite for the initiation of cellular immune responses. Here we report the mechanisms controlling the recognition and uptake of polymeric PGNs by circulating human mononuclear phagocytes. We found that complement C3 and C4 opsonins govern PGN recognition and internalization, but no single opsonin is indispensable due to multiple uptake redundancies. We observed a bimodal internalization of polymeric PGNs with distinct requirements for complement C4. At low PGN concentrations, C3 mediated PGN recognition by surface receptors while the efficient internalization of PGN polymers critically required C4. Supraphysiologic PGN concentrations triggered a secondary uptake modality that was insensitive to C4 and mediated instead by C3 engagement of complement receptors 1 and 3. To our knowledge this is the first description of non-overlapping C3 and C4 opsonophagocytoses working in parallel. Controlling these uptake mechanisms has the potential to modulate PGN clearance and/or the dysregulated immune responses during bacterial infections.
Authors
Narcis I. Popescu, Jędrzej Kluza, Megan A. Reidy, Elizabeth Duggan, John D. Lambris, Linda F. Thompson, K. Mark Coggeshall
Abstract
BACKGROUND Current diagnostic tools for tuberculous pleural effusion (TPE) are often inadequate, making accurate diagnosis challenging. Effective identification of TPE is critical for ensuring proper treatment and preventing tuberculosis relapse. This study explored the potential of granzyme A (GZMA) as a biomarker for TPE.METHODS Patients with TPE, malignant pleural effusion (MPE), and parapneumonic pleural effusion (PPE) were recruited into discovery and validation cohorts. The discovery cohort consisted of 200 patients with TPE and 100 patients with MPE, while the validation cohort included 167 patients with TPE, 84 patients with MPE, and 69 patients with PPE.RESULTS In the discovery cohort, GZMA levels were significantly elevated in TPE compared with MPE, demonstrating 90% sensitivity and 91% specificity at a cutoff of 102.29 ng/mL for effectively distinguishing between the two conditions. In the validation cohort, GZMA maintained high diagnostic performance, distinguishing TPE from MPE with 87% sensitivity and 87% specificity and from PPE with 87% sensitivity and 84% specificity. Incorporating GZMA, lactate dehydrogenase (LDH), and adenosine deaminase (ADA) into a random forest model further improved diagnostic accuracy. In the discovery cohort, this model achieved 92% sensitivity and 100% specificity, and in the validation cohort, it distinguished TPE from MPE with 87% sensitivity and 94% specificity and from PPE with 87% sensitivity and 91% specificity.CONCLUSION Overall, GZMA is a promising biomarker for diagnosing TPE, with improved accuracy when combined with LDH and ADA, providing a robust tool for timely identification and effective management of patients with TPE.FUNDING The study was supported by Science and Technology Project of Shenzhen (KCXFZ20211020163545004, KQTD20210811090219022, JCYJ20220818095610021, JSGG20220822095200001, JCYJ20210324094614038), Shenzhen Medical Research Funding (B2302035, A2302004), Provincial Natural Science Foundation of Guangdong (2022A1515220034), and Shenzhen Third People’s Hospital Research Foundation (G2022155).
Authors
Fuxiang Li, Chuanzhi Zhu, Yue Zhang, Fanhui Kong, Ximeng Zhang, Liping Pan, Hongyan Jia, Liang Fu, Yunlong Hu, Guofang Deng, Qianting Yang, Xinchun Chen, Yi Cai
No posts were found with this tag.
