Search

Introduction Classically IgA in the gut prevents the invasion of microorganisms to systemic organs through the process of neutralization and immune exclusion. Interestingly, recent reports suggest that IgA might help in biofilm formation and promote bacterial growth inside the intestine. Methods In this study, we used flow cytometry, ELISA and chemical models of colitis to test whether the quality and quantity of IgA can select for bacterial persistence in the gut. Results We found that members of Proteobacteria such as γ-Proteobacteria and SFB are preferentially coated by IgA in WT mice. In partial absence of either T-dependent or T-independent IgA responses, there are no significant differences in the frequency of bacteria coated with IgA in mice. However, in, Rag-/- mice that lack all antibodies, had a severe reduction in Proteobacteria and were resistant to DSS induced colitis, suggesting that secretory IgA might be essential for differential retention of these taxa in the mouse gut. Rag-/- littermates in the F2 generation generated from (B6 x Rag-/-) F1 mice acquired the underrepresented bacteria taxa such as γ-Proteobacteria through vertical transmission of flora and died soon after weaning possibly due to the acquired flora. Additionally, continued exposure of Rag-/- mice to B6 flora by cohousing mice led to the acquisition of γ-Proteobacteria and to mortality. Conclusion Together, our results indicate that host survival in the complete absence of an IgA response necessitates the exclusion of certain bacterial taxa from the gut microbiome.

The coronavirus disease (COVID-19) is a highly contagious viral illness caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). COVID-19 has had a catastrophic effect globally causing millions of deaths worldwide and causing long-lasting health complications in COVID-19 survivors. Recent studies including ours have highlighted that adipose tissue can act as a reservoir where SARS-CoV-2 can persist and cause long-term health problems. Here, we evaluated the effect of SARS-CoV-2 infection on adipose tissue physiology and the pathogenesis of fat loss in a murine COVID-19 model using humanized angiotensin-converting enzyme 2 (hACE2) mice. Since epidemiological studies reported a higher mortality rate of COVID-19 in males than in females, we examined hACE2 mice of both sexes and performed a comparative analysis. Our study revealed for the first time that: (a) viral loads in adipose tissue and the lungs differ between males and females in hACE2 mice; (b) an inverse relationship exists between the viral loads in the lungs and adipose tissue, and it differs between males and females; and (c) CoV-2 infection alters immune signaling and cell death signaling differently in SARS-CoV-2 infected male and female mice. Overall, our data suggest that adipose tissue and loss of fat cells could play important roles in determining susceptibility to CoV-2 infection in a sex-dependent manner.

Tuberculosis (TB) is a highly infectious bacterial disease that primarily attacks the lungs. TB is manifested either as latent TB infection (LTBI) or active TB disease, the latter posing a greater threat to life. The risk of developing active TB disease from LTBI is three times higher in individuals with type 2 diabetes mellitus (T2DM). The association between TB and T2DM is becoming more prominent as T2DM is rapidly increasing in settings where TB is endemic. T2DM is a chronic metabolic disorder characterized by elevated blood glucose, insulin resistance, and relative insulin deficiency. Insulin resistance and stress-induced hyperglycemia have been shown to be increased by TB and to return to normal upon treatment. Previously, we demonstrated that adipocytes (or fat tissue) regulate pulmonary pathology, inflammation, and Mycobacterium tuberculosis (Mtb) load in a murine model of TB. Metabolic disturbances of adipose tissue and/or adipocyte dysfunction contribute to the pathogenesis of T2DM. Thus, pathological adipocytes not only regulate pulmonary pathology, but also increase the risk for T2DM during TB infection. However, the cellular and molecular mechanisms driving the interaction between hyperglycemia, T2DM and TB remain poorly understood. Here, we report the impact of Mtb infection on the development of insulin resistance in mice fed on a regular diet (RD) versus high-fat diet (HFD) and, conversely, the effect of hyperglycemia on pulmonary pathogenesis in juvenile and adult mouse models. Overall, our study demonstrated that Mtb persists in adipose tissue and that Mtb infection induces irregular adipocyte lipolysis and loss of fat cells via different pathways in RD- and HFD-fed mice. In RD-fed mice, the levels of TNFα and HSL (hormone sensitive lipase) play an important role whereas in HFD-fed mice, ATGL (adipose triglyceride lipase) plays a major role in regulating adipocyte lipolysis and apoptosis during Mtb infection in adult mice. We also showed that Mtb infected adult mice that were fed an RD developed insulin resistance similar to infected adult mice that were overweight due to a HFD diet. Importantly, we found that a consequence of Mtb infection was increased lipid accumulation in the lungs, which altered cellular energy metabolism by inhibiting major energy signaling pathways such as insulin, AMPK and mToR. Thus, an altered balance between lipid metabolism and glucose metabolism in adipose tissue and other organs including the lungs may be an important component of the link between Mtb infection and subsequent metabolic syndrome.

Coronavirus disease-2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2; CoV2) is a deadly contagious infectious disease. For those who survive COVID-19, post-COVID cardiac damage greatly increases the risk of cardiomyopathy and heart failure. Currently, the number of COVID-related cases are increasing in Latin America, where a major COVID comorbidity is Chagas' heart disease, which is caused by the parasite

BackgroundCoronavirus disease-2019 (COVID-19) caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2; CoV2) is a deadly contagious infectious disease. For those who survived COVID-19, post-COVID cardiac damage poses a major threat for the progression of cardiomyopathy and heart failure. Currently, the number of COVID-related cases and deaths are increasing in Latin America, where a major COVID comorbidity is Chagas’ heart disease (caused by the parasite Trypanosoma cruzi). Here, we investigated the effect of T. cruzi infection on the pathogenesis and severity of CoV2 infection and, conversely, the effect of CoV2 infection on heart pathology during coinfection.Methodology/findingsWe used transgenic human angiotensin-converting enzyme 2 (huACE2) mice infected with CoV2, T. cruzi, or coinfected with both in this study. Our study shows for the first time that white adipose tissue (WAT) serves as a reservoir for CoV2 and the persistence of CoV2 in WAT alters adipose tissue morphology and adipocyte physiology. Our data demonstrate a correlation between the loss of fat cells and the pulmonary adipogenic signaling (via adiponectin isomers) and pathology in CoV2 infection. The viral load in the lungs is inversely proportional to the viral load in WAT, which differs between male and female mice. Our findings also suggest that adiponectin-PPAR signaling may differently regulate Chagas cardiomyopathy in coinfected males and females.ConclusionWe conclude that adipogenic signaling may play important roles in cardio-pulmonary pathogenesis during CoV2 infection and T. cruzi coinfection. The levels of adiponectin isomers differ between male and female mice during CoV2 infection and coinfection with T. cruzi, which may differently regulate inflammation, viral load, and pathology in the lungs of both the sexes. Our findings are in line with other clinical observations that reported that males are more susceptible to COVID-19 than females and suffer greater pulmonary damage.

The immunological roles of the nuclear factor-kappaB (NF-κB) pathway are mediated via the canonical components in immune responses and via non-canonical components in immune organogenesis and homeostasis, although the two components are capable of crosstalk. Regulatory CD4 T cells (Tregs) are homeostatically functional and represent an interesting potential meeting point of these two NF-κB components. We show that mice deficient in the non-canonical NF-κB component gene Nfkb2 (p100) had normal thymic development and suppressive function of Tregs. However, they had enhanced frequencies of peripheral ‘effector-phenotype’ Tregs (eTregs). In bi-parental chimeras of wild-type (WT) and Nfkb2−/− mice, the Nfkb2−/− genotype was over-represented in Tregs, with a further increase in the relative prominence of eTregs. Consistent with distinct properties of eTregs, the Nfkb2−/− genotype was more prominent in Tregs in extra-lymphoid tissues such as liver in the bi-parental chimeras. The Nfkb2−/− Tregs also displayed greater survival, activation and proliferation in vivo. These Nfkb2−/− Tregs showed higher nuclear NF-κB activity mainly comprising of RelB-containing dimers, in contrast to the prominence of cRel- and RelA-containing dimers in WT Tregs. Since p100 is an inhibitor of RelB activation as well as a participant as cleaved p52 in RelB nuclear activity, we tested bi-parental chimeras of WT and Relb−/− mice, and found normal frequencies of Relb−/− Tregs and eTregs in these chimeric mice. Our findings confirm and extend recent data, and indicate that p100 normally restrains RelB-mediated Treg activation, and in the absence of p100, p50-RelB dimers can contribute to Treg activation.

The induction of CD80 on podocytes has been shown in animal models of podocyte injury and in certain cases of nephrotic syndrome. In a lipopolysaccharide (LPS)-induced mouse model of albuminuria, we have recently shown a signalling axis of LPS-myeloid cell activation-TNFα production-podocyte CD80 induction-albuminuria. Therefore, in this report, we investigated the cellular and molecular consequences of TNFα addition and CD80 expression on cultured podocytes. A murine podocyte cell line was used for TNFα treatment and for over-expressing CD80. Expression and localization of various podocyte proteins was analysed by reverse transcriptase-polymerase chain reaction, western blotting and immunofluorescence. HEK293 cells were used to biochemically characterize interactions. Podocytes treated with LPS in vitro did not cause CD80 upregulation but TNFα treatment was associated with an increase in CD80 levels, actin derangement and poor wound healing. Podocytes stably expressing CD80 showed actin derangement and co-localization with Neph1. CD80 and Neph1 interaction was confirmed by pull down assays of CD80 and Neph1 transfected in HEK293 cells. Addition of TNFα to podocytes causes CD80 upregulation, actin reorganization and podocyte injury. Overexpressed CD80 and Neph1 interact via their extracellular domain. This interaction implies a mechanism of slit diaphragm disruption and possible use of small molecules that disrupt CD80-Neph1 interaction as a potential for treatment of nephrotic syndrome associated with CD80 upregulation.

Transient albuminuria induced by pathogen-associated molecular patterns (PAMPs) in mice through engagement of Toll-like receptors (TLRs) is widely studied as a partial model for some forms of human nephrotic syndrome (NS). In addition to TLRs, CD80 has been shown to be essential for PAMP-mediated albuminuria. However, the mechanistic relationships between TLRs, CD80 and albuminuria remain unclear. Here, we show that albuminuria and CD80-uria induced in mice by many TLR ligands are dependent on the expression of TLRs and their downstream signalling intermediate MyD88 exclusively in hematopoietic cells and, conversely, on CD80 expression exclusively in non-hematopoietic cells. TNFα is crucial for TLR-mediated albuminuria and CD80-uria, and induces CD80 expression in cultured renal podocytes. IL-10 from hematopoietic cells ameliorates TNFα production, albuminuria and CD80-uria but does not prevent TNFα-mediated induction of podocyte CD80 expression. Chitohexaose, a small molecule originally of parasite origin, mediates TLR4-dependent anti-inflammatory responses, and blocks TLR-mediated albuminuria and CD80-uria through IL-10. Thus, TNFα is a prominent mediator of renal CD80 induction and resultant albuminuria in this model, and small molecules modulating TLR-mediated inflammatory activation might have contributory or adjunct therapeutic potential in some contexts of NS development., Summary: Systemic TNFα mediates myeloid cell and podocyte cross-talk to cause LPS-induced mouse microalbuminuria, a partial model of human nephrotic syndrome, pointing to potential adjunct therapeutic approaches.

The present study explores the differential utility of 'Popular stories' to relieve distress as perceived by persons with chronic physical illness and mental illness and also to examine the differential utility of various themes of stories. Each of the sample group consisting of persons with HIV+, Cancer, Depression spectrum disorders, Anxiety spectrum disorders, and also persons without any specific illness (N = 125) was presented with a set of 40 stories of eight different themes. They were asked to rate the utility of each story to relieve distress. Qualitative observations during the process were also noted down. Persons with chronic physical illness, especially those with HIV+, have given the highest rating to the usefulness of stories for relieving distress vis-a-vis persons with mental illness, especially Anxiety group. Stories with the theme 'Goal Direction and Prioritization' were perceived most useful for relieving distress whereas the theme 'Relativity/Count your blessings' has been perceived as the least useful for relieving distress. The findings of the present study would be useful in selection of stories to be used in a psychotherapeutic set-up and further investigation.

Reports indicate that, variously, 10–50% of bacteria in the gut are coated with IgA and that bacterial diversity correlates with IgA amounts. In support of these observations, it was recently shown that there is an overall reduction in bacterial diversity in Rag1−/− mice. In extension to these findings, we report that taxa that are severely depleted in Rag1−/− mice include Proteobacteria and SFB, which are IgA-coated in wild-type (WT) mice. We reasoned that IgA might be required for these taxa to take up residence in the gut. Further, since germ-free SCID mice can be stably colonized with SFB, we explored the possibility that retention of SFBs may require continuous exposure to the organisms. We tested this by co-housing Rag1−/− mice with WT mice and found that by day 5, Rag1−/− mice had acquired both Proteobacteria and SFB. In addition, when F2 littermates obtained from WT x Rag1−/− crosses were compared for microbial diversity, both were present in the Rag1−/− pups. These data raise the possibility that mice are being colonized continuously. We also report that members of Proteobacteria separate equally into IgA-bound and IgA-unbound fraction, raising the possibility that the IgA-unbound fraction may represent new colonizers. Finally, in agreement with earlier reports, which showed that transfer of IgA-coated bacteria increases the susceptibility to DSS-colitis in germ-free mice, we find that Rag1−/− mice, which lack coated bacteria, are more resistant to DSS-colitis.

Following Japanese encephalitis virus (JEV) infection neutralizing antibodies are shown to provide protection in a significant proportion of cases, but not all, suggesting additional components of immune system might also contribute to elicit protective immune response. Here we have characterized the role of T cells in offering protection in adult mice infected with JEV. Mice lacking α/β–T cells (TCRβ–null) are highly susceptible and die over 10–18 day period as compared to the wild-type (WT) mice which are resistant. This is associated with high viral load, higher mRNA levels of proinflammatory cytokines and breach in the blood-brain-barrier (BBB). Infected WT mice do not show a breach in BBB; however, in contrast to TCRβ-null, they show the presence of T cells in the brain. Using adoptive transfer of cells with specific genetic deficiencies we see that neither the presence of CD4 T cells nor cytokines such as IL-4, IL-10 or interferon-gamma have any significant role in offering protection from primary infection. In contrast, we show that CD8 T cell deficiency is more critical as absence of CD8 T cells alone increases mortality in mice infected with JEV. Further, transfer of T cells from beige mice with defects in granular lytic function into TCRβ-null mice shows poor protection implicating granule-mediated target cell lysis as an essential component for survival. In addition, for the first time we report that γ/δ-T cells also make significant contribution to confer protection from JEV infection. Our data show that effector CD8 T cells play a protective role during primary infection possibly by preventing the breach in BBB and neuronal damage., Author summary Japanese encephalitis virus (JEV) commonly infects human beings in developing countries including those in Southeast Asia. While the majority of the infected people suffer from mild illness, a minority suffers from encephalitis which may lead to death. The virus is transmitted by mosquito bites and elimination of mosquitoes is not a practical answer to prevent the disease, therefore, prevention by vaccination is a desired goal. While various vaccines are clinically tried and some are marketed further improvement in vaccines is still possible. In a complex disease like JE many components of the immune system contribute to variable extent in protection. We show here that one subset of T cells called CD8 cells which are capable of killing infected cells are very critical for providing protection against JEV infection in mice. In the absence of T cells we also observed that virus reaches the brain early, unlike in the presence of T cells, and this possibly results in high virus load in the brain leading to worsening of the condition and death. Thus, our data help in identifying the role of CD8 T cells in protection from lethal JEV infection and the information may be useful for modifying and/or developing vaccine for prevention of JEV-mediated disease.