bluuebunny/crossref_metadata_2025_split huggingface dataset:
Wnt4 controls early cDC1 commitment to suppress Type 2 immunity
Authors: Hung Li-Yin , Johnson John L , Ji Yingbiao , Christian David A , Herbine Karl R , Pastore Christopher F , Herbert De’Broski R 
Published: January 2023

Abstract
Whether conventional dendritic cells (cDC) acquire subset identity under direction of regenerative glycoproteins is unknown. We demonstrate that Wnt4, a beta-catenin independent Wnt ligand, is necessary and sufficient for pre-cDC1 BM specification. CD11c-restricted Wnt4 deficiency reduced mature cDC1 numbers in BM, spleen, lung, and intestine and Wnt4 directly induced of pJNK activation and cDC1 commitment. CD11cCreWnt4flox/flox mice lacked IRF8/cJun complex stabilization and had increased basal numbers of cDC2, group 2 innate lymphoid cells ILC2 and increased resistance to the parasite Nippostrongylus brasiliensis compared to CD11cCre controls. These data reveal a novel role for Wnt4 in DC commitment and pathogen-specific immunity.
Isolation of a 31 kDa protein in Angiostrongylus cantonensis from Hawaii and its comparative diagnostic efficacy to the 31 kDa protein from Thailand and crude antigen from Hawaii
Authors: Jarvi Susan Irene , Snook Kirsten Anna , Cannoles Kirsten , Quarta Stefano , Eamsobhana Praphathip , Shepherd Laura , Tagami Yaeko , Kaluna Lisa , Howe Kathleen , Jacquier Steven , Niebuhr Christopher , Bicakci Dehiz 
Published: January 2023

Abstract
The zoonotic metastrongylid nematode Angiostrongylus cantonensis is the primary cause of eosinophilic meningitis worldwide. East Hawaii Island is considered the US epicenter of the disease, also known as rat lungworm, and presentation is often severe. In 2015 we collected 435 blood samples and questionnaires from human volunteers for a pilot study on the prevalence of A. cantonensis in East Hawaii Island. Serum was tested by ELISA with crude antigen from Hawaii nematodes and by dot-blot ELISA with 31 kDa proteins isolated from Thailand nematodes. In the current study, consent was obtained from 199 of the original participants for the use of their previously collected samples. Nematodes were collected from the lungs and pulmonary arteries of rats in the course of animal studies, and SDS-PAGE gels were used to isolate the Hawaii 31 kDa proteins. The proteins were quantified with size determination by bioanalysis. The three different serological methods were compared. Of volunteers who defined themselves as definitively diagnosed by a clinician (n = 12), 40% were positive by Hawaii (HI) 31 kDa ELISA and reported being infected in or after 2004. Of those self-reported as previously infected with A. cantonensis (n=19), 31.5% were positive by HI 31 kDa ELISA; those who self-reported as uninfected (n=124), 22% tested positive by HI 31 kDa ELISA. The HI 31 kDa proteins showed an overall seroprevalence of 25% in the population, while the Thailand isolate of 31 kDa showed 30% and the HI crude antigen ELISA showed 22% prevalence, demonstrating that these antigens may have diagnostic efficacy.
Adherence of local isolates of Candida species to vaginal epithelial cells of apparently healthy and HIV-infected women in Nigeria, and pro-inflammatory cytokines response in a mouse model
Authors: Emele Felix Emele , Anieto Ezinne Chinenye 
Published: January 2023

Abstract

Background
Candida albicans (CA) has long been considered as the commonest cause of vulvovaginal candidiasis (VVC), while non-albicans Candida species (NAC) are mainly involved in opportunistic infections, particularly in HIV/AIDS. A prerequisite for colonization and eventual invasion of vaginal mucosa is the ability of Candida to adhere to vaginal epithelial cells (VECs); subsequent production of proinflammatory cytokines, such as IL-1β, IFN-γ, and IL-17, plays key roles in antifungal activity in the mucosa. Recent reports suggest increasing importance of non-albicans Candida species in VVC, in our region. This raised the need to compare the capacity of the local isolates of CA and NAC to adhere to VECs, and to elicit key inflammatory cytokines in mouse model.

Materials and Methods
Vaginal Epithelial Cells were collected from apparently healthy non-pregnant women, as well as those having HIV infection (n=16). The VECs were exposed to 12 local isolates of CA and NAC, in adherence assay. Mice were intra-vaginally inoculated with the Candida species and assayed for IL-1β, IL-17 and IFN-γ after 14 days.

Results
More NAC yeasts adhered to VECs of HIV infected women (Mean value = 5.6±3.8) than CA (2.7±3.3). Mean adherence of Candida to VECs from other sources were: HIV infected women with VVC (NAC = 6.2±4.7; CA = 5.1±1.7); apparently healthy women (CA = 2.90±3.40; NAC = 2.8±2.0). Mean levels (ng/ml) of IL-17 produced were: NAC (0.16±0.01) and CA (0.13±0.01).

Conclusion
Results tend to suggest that NAC is now as important as CA in VVC, and that pre-sensitization of VECs (of HIV+ women) increased Candida adherence. Depletion of IL-17 producing CD4+ cells could partly explain the preponderance of NAC in HIV/AIDS fungal opportunistic infections.
Aging impairs the cellular immune response to acute C. difficile infection
Authors: Close Lisa Abernathy , Dieterle Michael , Young Vincent 
Published: January 2023

Abstract
Clostridium difficile (C. difficile) is a spore-forming bacterium that produces enterotoxins that damage the intestinal epithelium. The incidence of C. difficile infection (CDI) increased significantly over the last two decades, particularly among those ≥65 years of age. The objective of this study was to determine the role of age in immune responses to C. difficile infection in mice, utilizing strains of varying virulence. We have shown that mice infected with C. difficile strain VPI 10463 (VPI) exhibit more severe disease compared to C. difficile strain 630. Thus, to examine an age-related effect on immune responses in CDI, young mice (2–3 months old) and aged mice (22–24 months old) were rendered susceptible with cefoperazone and then infected with either C. difficile strain 630 or VPI. Cecum and colon were harvested during peak disease severity (day 2–4 post-infection) and processed to assess intestinal immune cell profile by flow cytometry. We found that CD45+ immune cell infiltration occurs early in the cecum of mice infected with VPI, but not in 630, regardless of age. Of the CD45+ immune cells in the cecum and colon of VPI-infected mice, the majority were CD11b+ myeloid cells. While young mice infected with C. difficile strain VPI showed a robust increase in cecal eosinophils, there was a significant lack of an eosinophil response in aged counterparts. In summary, C. difficile strain 630 did not elicit an early cellular intestinal immune response and this was independent of age. Furthermore, aged mice demonstrated a significantly decreased local cellular immune response to C. difficile VPI 10463 infection compared to young mice, suggesting a role for age-associated immune responses in CDI outcomes in older patient populations.
NKp46+ NK cells regulate brain CD4+ T cells to promote chronic Toxoplasma gondii infection
Authors: Gigley Jason P. , Ivanova Daria L , Denton Stephen L 
Published: January 2023

Abstract
Reactivation of chronic Toxoplasma gondii (T. gondii) infection and toxoplasmic encephalitis is a major health concern in immune compromised people. Dysregulated T-cell responses are thought to promote chronic Toxoplasmosis. The non-T-cell factors that contribute to T cell dysregulation and chronic T. gondii infection are unclear. We have discovered that NKp46+ NK cells paradoxically increase the frequency and number of IFNγ+TNFα+CD4+ T-cells in the brain in during chronic T. gondii infection. Depletion of NK cells resulted in a decrease in polyfunctional brain CD4+ T-cells and an increase in IFNγ+Grzb+CD8+ T-cell responses in the brain. This decrease in CD4+ T-cell and increase in CD8+ T-cell responses correlated with better survival of chronically infected mice. This result suggests that NKp46+ NK cells drive an NK cell-dependent CD4+ T cell response that is detrimental to the CD8+ T cell response important for controlling chronic T. gondii infection. In support of this possibility, adoptive transfer of NK cell-dependent CD4+ T cells into chronically infected mice reduced polyfunctional CD8+ T-cell responses in the brain while CD4+ T cells generated in the absence of NK cells during chronic T. gondii infection did not. NKp46+ NK cells were not found in brain tissue, but appear to localize to the vasculature of the brain and periphery during chronic T. gondii infection. Surprisingly, we observe that NKp46+ NK cells increase their expression of MHC Class II. Our results lead us to hypothesize that during chronic T. gondii infection NKp46+ NK cells acquire the ability to prime CD4+ T-cell responses via MHC Class II expression resulting in decreased polyfunctional CD8 T cell responses to promote parasite persistence.
THE IL-12- AND IL-23-DEPENDENT NK-CELL RESPONSE IS ESSENTIAL FOR PROTECTIVE IMMUNITY AGAINST SECONDARY TOXOPLASMA GONDII INFECTION
Authors: Denton Stephen L , Ivanova Daria L , Mundhenke Tiffany , Gigley Jason P. 
Published: January 2023

Abstract
Natural Killer (NK) cells can develop memory-like features and contribute to long-term immunity in mice and humans. NK cells are critical for protection against acute T. gondii infection. However, whether they contribute to long-term immunity in response to this parasite is unknown. We used a vaccine challenge model of parasite infection to address this question and to define the mechanism by which NK cells are activated during secondary parasite infection. We found NK cells were required for control of secondary infection. NK cells increased in number at the infection site, became cytotoxic and produced IFNγ. Adoptive transfer and NK-cell fate mapping revealed that T. gondii-experienced NK cells were not intrinsically different from naïve NK cells with respect to their long-term persistence and ability to protect. Thus, they did not develop memory-like characteristics. Instead, a cell-extrinsic mechanism may control protective NK-cell responses during secondary infection. To test the involvement of a cell-extrinsic mechanism, we used anti-IL-12p70 depletion and IL-12p35−/− mice and found that the secondary NK-cell response was not fully dependent on IL-12. IL-23 depletion with anti-IL-23p19 in vivo significantly reduced the secondary NK-cell response, suggesting that both IL-12 and IL-23 were involved. Anti-IL-12p40 treatment, which blocks both IL-12 and IL-23, eliminated the protective secondary NK-cell response, supporting this hypothesis. Our results define a previously unknown protective role for NK cells during secondary T. gondii infection that is dependent on both IL-12 and IL-23.
Innate and adaptive immune interactions in Coccidioides infection
Authors: Hoyer Katrina K , Diep Anh 
Published: January 2023

Abstract
Protective immunity against the fungal pathogen Coccidioides requires specific T helper cellular responses. Mouse infection and vaccine studies have defined CD4 T helper (Th)1 and Th17 cells in the resolution of infection and in effective protection, while patients with chronic Coccidioides infection demonstrate reduced cellular responses. Several gaps in knowledge preclude our ability to develop new diagnostics and therapeutics for treating this infection. Little is known about the microenvironment in human lung tissue during infection, and the types of immune cells that promote effective control of the fungus within this specialized location. How variations on local immune populations alter disease severity and ability of the fungus to disseminate have not been explored. We recently identified several peripheral blood biomarkers during acute infection that distinguish pediatric patients that resolve infection from those that develop chronic disease. Patients with chronic disease had reduced Th17 and elevated Treg frequencies compared to patients that resolved disease. The inability to clear Coccidioides infection may be a result of elevated Treg frequency and functional capacity, or of skewed effector differentiation. We use mouse Coccidioides infection and in vitro culture assays to uncover the host immune players that promote effective immunity, and to identify fungal morphology changes and fungal burden differences at the innate and adaptive immune interface.
ICOS expression is not required for memory T cell formation or maintenance, but does promote Tfh cell differentiation and the humoral response after secondary Plasmodium chabaudi chabaudi AS infection
Authors: Latham Leah E , Wikenheiser Daniel J , Stumhofer Jason S 
Published: January 2023

Abstract
In addition to promoting follicular helper T (Tfh) cell development, ICOS is implicated in memory T cell formation. We have shown in the P. chabaudi rodent model of malaria that the absence of ICOS leads to a persistent non-resolving infection due to a defect in Tfh cell maturation that prevents the formation of a germinal center (GC) response. Here we show that memory T cell formation and maintenance is not impaired in the absence of ICOS. The presence of CXCR5-expressing central memory T (TCM) cells in Icos−/− mice suggests that they are capable of differentiating into Tfh cells and supporting the humoral response after challenge. However, the formation of Tfh cells was impaired in Icos−/− mice after challenge. Similar to the primary infection, drug-cleared Icos−/− mice displayed a relapsing parasitemia that occurred more frequently and with higher peaks compared to wild-type mice, which was associated with a diminished and delayed parasite-specific antibody response and the absence of GCs. Surprisingly, GCs that were present in the spleen of wild-type mice pre-challenge dispersed shortly after challenge, but were apparent again by day 35 post-challenge. Adoptive transfer of TCM cells from wild-type and Icos−/− mice into Tcrβ−/− mice to directly evaluate the ability of TCM cells to differentiate into Tfh cells revealed that CXCR5+ and CXCR5− TCM cells from wild-type mice could develop into Tfh cells in the presence or absence of memory B cells. However, TCM cells from Icos−/− mice were incapable of differentiating into Tfh cells, although they could support GC-independent Ab production. Thus, ICOS expression is not required for memory T cell formation, but is necessary for the differentiation of TCM cells into Tfh cells after challenge.
Tuberculosis boosts HIV-1 production by macrophages through IL-10/STAT3 dependent tunneling nanotube formation
Authors: Lugo Geanncarlo , Souriant Shanti , Balboa Luciana , Dupont Maeva , Pingris Karine , Kviatcovsky Denise , Cougoule Celine , Lastrucci Claire , Bah Aicha , Gasser Roman , Poincloux Renaud , Raynaud-Messina Brigitte , Al Saati Talal , Inwentarz Sandra , Poggi Susana , Moraña Eduardo Jose , González-Montaner Pablo , Corti Marcelo , Lagane Bernard , Vergne Isabelle , Allers Carolina , Kaushal Deepak , Kuroda Marcelo , del Carmen Sasiain Maria , Neyrolles Olivier , Maridonneau-Parini Isabelle , Verollet Christel 
Published: January 2023

Abstract
The tuberculosis (TB) bacillus, Mycobacterium tuberculosis (Mtb) and HIV-1 are known to act synergistically, however, the mechanisms by which Mtb exacerbates HIV-1 pathogenesis are not well known. Using in vitro and ex vivo cell culture system, we show that human M(IL-10) anti-inflammatory macrophages, present in TB-associated microenvironments, produced high levels of HIV-1. In vivo, M(IL-10) macrophages were expanded in lungs of co-infected non-human primates, their number correlated with disease severity, and markers for these cells (soluble CD163 and MerTK) accumulated in the blood of co-infected patients. These M(IL-10) macrophages formed direct cell-to-cell bridges, which we identified as tunneling nanotubes (TNTs) involved in viral transfer. TNT formation required the IL-10/STAT3 signaling pathway, and targeted inhibition of TNTs substantially reduced the enhanced HIV-1 cell-to-cell transfer and overproduction in M(IL-10) macrophages. Our study reveals that TNTs facilitate viral transfer and amplification, promoting TNT formation as a mechanism to be explored in TB/AIDS potential therapeutics.
Induction of inflammatory responses in splenocytes by exosomes released from intestinal epithelial cells following Cryptosporidium parvum infection
Authors: Chen Xian-Ming , Wang Yang , Shen Yujuan , Liu Hua , Yin Jianhai , Zhang Xin-Tian , Gong Ai-Yu , Chen Xiqiang , Chen Siyi , Mathy Nicholas W , Cao Jianping 
Published: January 2023

Abstract
Cryptosporidium, a protozoan parasite that infects the gastrointestinal epithelium and other mucosal surfaces in humans and animals, is an important opportunistic pathogen in AIDS patients and one of the most common enteric pathogens affecting young children in developing regions. We previously demonstrated that C. parvum infection stimulates host epithelial cells to release exosomes and these released exosomes shuttle several antimicrobial peptides to carry out anti-C. parvum activity. Murine intestinal epithelial (IEC4.1) cells and neonatal mice were applied for infection. Primary splenocytes were exposed to exosomes isolated from infected cells or un-infected controls. Inflammatory response in splenocytes were measured. We detected upregulation of inflammatory genes in the liver and spleen following C. parvum intestinal infection in neonatal mice. Interestingly, exosomes released from intestinal epithelial cells following C. parvum infection could activate the nuclear factor kappa B signaling pathway and trigger inflammatory gene transcription in isolated primary splenocytes. Several epithelial cell-derived proteins and a subset of parasite RNAs were detected in the exosomes released from C. parvum-infected intestinal epithelial cells. Shuttling of these effector molecules, including the high mobility group box 1 protein, was involved in the induction of inflammatory responses in splenocytes induced by the released exosomes from infected cells. Our data indicate that exosomes released from intestinal epithelial cells upon C. parvum infection can activate immune cells through shuttling various effector molecules, a process that may be relevant to host systemic responses to Cryptosporidium infection.
Microbiota-derived butyrate limits the autoimmune response by promoting follicular regulatory T cells
Authors: Takahashi Daisuke , Hoshina Naomi , Clarke Julie M. , Hase Koji 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is a chronic debilitating autoimmune disorder with a high prevalence, especially in industrialized countries. Dysbiosis of the intestinal microbiota has been observed in RA patients. For instance, new-onset untreated RA is associated with the expansion of Prevotellaceae and the under representation of the Clostridiumcluster XIVa, including Lachnospiraceae, which are major butyrate producers in the gut, although the pathological relevance has remained obscure. Here, we report that microbiota fermentation product butyrate controls the development of autoimmune arthritis in the host. We found that systemic autoantigen immunization causes hyperplasia of gut-associated lymphoid tissues by amplifying the germinal center (GC) reaction. Butyrate mitigated these pathological events by increasing Bcl-6+CXCR5+CD25−Foxp3+ follicular regulatory T (TFR) cells. Butyrate directly induced the differentiation of functional TFR cells by enhancing histone acetylation in TFR cell marker genes. The adoptive transfer of butyrate-induced TFR cells prevented autoimmune arthritis in mice. Notably, TFR cells induced by butyrate suppressed the development of autoreactive follicular helper T (TFH) and GCB cells and their migration from GALT into articulation-draining lymph nodes (DLNs). Accordingly, microbiota-derived butyrate serves as an environmental cue to enhance TFR cells which suppress the GC reaction and autoantibody production in the systemic lymphoid tissue, eventually ameliorating autoimmune arthritis. Our findings provide mechanistic insights into the link between the gut microbiota and RA risk.
Functional characterization of the enteric animal virome
Authors: Dallari Simone , Heaney Thomas , Rosas Adriana , Cadwell Ken 
Published: January 2023

Abstract
The enteric virome includes viruses that infect eukaryotic cells in the gut and is one constituent of the mammalian microbiome. Although best known for causing acute diarrheal disease, many of these viruses are detected in asymptomatic individuals. The immune consequence of harboring these viruses is unclear. We recently demonstrated that norovirus infection promotes the development of the mucosal immune system in mice in a manner similar to symbiotic bacteria, and can protect against models of chemical and microbial injury. These results are reminiscent of findings from the microbiome field demonstrating that intestinal colonization by individual bacterial species directs the differentiation of the immune system. Here, we examined the extent to which the eukaryotic enteric virome contributes to the state of the host immune system. Examination of 10 enteric DNA and RNA viruses, representing 6 viral families, revealed that many establish prolonged infection in the absence of disease. To evaluate the immunological impact of these viral infections that occurs independently of other members of the microbiome, we performed a comprehensive flow cytometry analysis of several organs following infection of germ-free mice that assessed over 20 immune cell subsets and their capacity for cytokine production. We found profound effects of enteric viral infection in all the tissues tested, showing strain-specific responses, such as norovirus-induced expansion of type 1 regulatory T cells, and commonly shared ones, such as the increased potential of colonic T cells to produce Il-22. Taken together, these data demonstrate that enteric virome members contribute to the immune status of the host.
IL-6, IL-8 drive LAG3/PD1 immune suppression on effector and naïve, peripheral blood CD8+ T cells in cancer patients
Authors: Somasundaram Ashwin , Cillo Anthony , Oliveri Lauren , Herman James , Kirkwood John , Ferris Robert L , Bruno Tullia Carmela , Vignali Dario 
Published: January 2023

Abstract
Cancer patients off therapy and with normal white blood cell counts are often at greater risk for infections, immune dysregulation, progressive disease or reactivation of viral infections. However, the exact mechanism of this systemic immunosuppression in cancer patients is not fully understood. We hypothesize that cancer patients may have systemic immune suppression via cytokine-driven IR expression in all CD8+ T cells subsets, including naïve cells.
PBL were obtained from healthy donors and treatment-naïve NSCLC, HNSCC, and melanoma patients. IR (i.e. LAG3, PD1, CTLA4, etc) expression was assessed on CD8+ T cells, CD4+ T cells, and regulatory T cells. Plasma cytokine concentrations were compared by Luminex. Autologous micro-stimulation assays were performed on peripheral CD8+ or CD4+ T cells with antigen presenting cells plus or minus IR blockade.
CD8+ T cells, including naive CD8+ T cells, from cancer patient PBL contain elevated total LAG3 expression which correlated with worse state, worse survival, and elevated expression of other IRs. Further, CD8+ T cells from these patients had decreased proliferation, which was rescued with the addition of anti-LAG3 or anti-PD1. Plasma from these patients had significantly elevated levels of cytokines that can signal via STAT3 (i.e. IL-6, IL-8), which were independently found to increase total IR expression in healthy donor, naïve CD8+ T cells.
Patients with cancer have systemic elevations IL-6 and IL-8 leading to increased IR expression in naïve, peripheral CD8+ T cells making them poised for exhaustion even before TCR binding. These findings suggest that cytokine combined with IR blockade may play a role in reversing PD1 blockade resistance.