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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.

Chronic Chagas cardiomyopathy (CCC) caused by a parasite Trypanosoma cruzi is a life-threatening disease in Latin America, for which there is no effective drug or vaccine. The pathogenesis of CCC is complex and multifactorial. Previously, we demonstrated T. cruzi infected mice lose a significant amount of fat tissue which correlates with progression of CCC. Based on this an investigation was undertaken during both acute and chronic T. cruzi infection utilizing the FAT-ATTAC murine model (that allows modulation of fat mass) to understand the consequences of the loss of adipocytes in the regulation of cardiac parasite load, parasite persistence, inflammation, mitochondrial stress, ER stress, survival, CCC progression and CCC severity. Mice were infected intraperitoneally with 5x104 and 103 trypomastigotes to generate acute and chronic Chagas models, respectively. Ablation of adipocytes was carried out in uninfected and infected mice by treatment with AP21087 for 10 days starting at 15DPI (acute infection) and at 65DPI (indeterminate infection). During acute infection, cardiac ultrasound imaging, histological, and biochemical analyses demonstrated that fat ablation increased cardiac parasite load, cardiac pathology and right ventricular dilation and decreased survival. During chronic indeterminate infection ablation of fat cells increased cardiac pathology and caused bi-ventricular dilation. These data demonstrate that dysfunctional adipose tissue not only affects cardiac metabolism but also the inflammatory status, morphology and physiology of the myocardium and increases the risk of progression and severity of CCC in murine Chagas disease., Author summary An estimated eight million individuals worldwide are chronically infected with Trypanosoma cruzi, the causative agent of Chagas disease (CD). Of these infected individuals, 30% will develop chronic Chagas cardiomyopathy (CCC), a major cause of morbidity and mortality in CD endemic regions for which there is currently no effective drug or vaccine. The molecular mechanisms underlying CCC pathogenesis, progression and severity are complex, multi-factorial and not completely understood. Earlier, it was demonstrated that T. cruzi persists in adipose tissue, alters adipocyte physiology, and causes loss of body fat mass in T. cruzi infected mice with CCC. In this study, the authors examined the role of visceral fat pad (adipose tissue) in regulating the pathogenic signalling in the development and progression of CCC using a fat mass modulatable transgenic mouse CD model. Loss of fat cells increased cardiac lipid load and deregulated cardiac lipid metabolism leading to mitochondrial oxidative stress and endoplasmic reticulum stress and severe CCC. In addition, loss of fat cells increased cardiac parasite load during acute infection and altered immune signalling in the hearts of infected mice during chronic infection. These discoveries underscore the importance of adipose tissue in the development of CCC.

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.

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.