transforming-growth-factor-beta and Viremia

SARS-CoV-2 viremia is associated with increased acute lung injury (ALI) and mortality in children and adults. The mechanisms by which viral components in the circulation mediate ALI in COVID-19 remain unclear. We tested the hypothesis that the SARS-CoV-2 envelope (E) protein induces Toll-like receptor (TLR)-mediated ALI and lung remodeling in a model of neonatal COVID-19. Neonatal C57BL6 mice given intraperitoneal E protein injections revealed a dose-dependent increase in lung cytokines [interleukin 6 (

Topics: Acute Lung Injury; Animals; Child; COVID-19; Endothelial Cells; Glucocorticoids; Humans; Lipopolysaccharides; Mice; Mice, Inbred C57BL; SARS-CoV-2; Toll-Like Receptor 2; Toll-Like Receptor 4; Toll-Like Receptors; Transforming Growth Factor beta; Viral Envelope; Viremia

We aimed to investigate the roles of cytokines during polyomavirus BK (BKV) reactivation in renal transplant patients. Forty-eight renal allograft recipients were enrolled, and their sera BKV viral load and mRNA expression levels of cytokines in peripheral blood mononuclear cells were measured by real-time polymerase chain reaction. Patient's age and gene expression levels of interleukin (IL)-2 (10.04 ± 2.63 vs. 8.70 ± 2.40, p = 0.049) and transforming growth factor (TGF)-β (12.58 ± 2.59 vs. 10.89 ± 1.91, p = 0.015) were significantly higher in BKV viremia (+) renal transplant patients. Multivariate logistic regression analysis revealed that age and mRNA expression levels of TGF-β, but not IL-2, significantly correlated with the presence of BKV viremia. Sera BKV viral loads showed a positive correlation with patient age and the levels of TGF-β and IL-6 mRNA. After adjusting for age and sex in the regression model, both age and TGF-β mRNA levels maintained a significant positive association with sera BKV viral loads. Serum TGF-β concentration tended to be higher in BKV viremia (+) patients (p = 0.079). In conclusion, expression levels of TGF-β were found to correlate with both BKV viremia positivity and sera BKV viral loads in renal transplant patients.

Topics: BK Virus; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Leukocytes, Mononuclear; Male; Middle Aged; Polyomavirus Infections; Postoperative Complications; Prognosis; Real-Time Polymerase Chain Reaction; Risk Factors; Transforming Growth Factor beta; Tumor Virus Infections; Viral Load; Viremia

The Vγ4(+) cells, a subpopulation of peripheral γδ T cells, are involved in West Nile virus (WNV) pathogenesis, but the underlying mechanism remains unclear. In this study, we found that WNV-infected Vγ4(+) cell-depleted mice had lower viremia and a reduced inflammatory response in the brain. The Vγ4(+) cells produced IL-17 during WNV infection, but blocking IL-17 signaling did not affect host susceptibility to WNV encephalitis. We also noted that there was an enhanced magnitude of protective splenic Vγ1(+) cell expansion in Vγ4(+) cell-depleted mice compared to that in controls during WNV infection. In addition, Vγ4(+) cells of WNV-infected mice had a higher potential for producing TGF-β. The γδ T cells of WNV-infected Vγ4(+) cell-depleted mice had a higher proliferation rate than those of WNV-infected controls upon ex vivo stimulation with anti-CD3, and this difference was diminished in the presence of TGF-β inhibitor. Finally, Vγ4(+) cells of infected mice contributed directly and indirectly to the higher level of IL-10, which is known to play a negative role in immunity against WNV infection. In summary, Vγ4(+) cells suppress Vγ1(+) cell expansion via TGF-β and increase IL-10 level during WNV infection, which together may lead to higher viremia and enhanced brain inflammation.

Topics: Animals; Brain; Female; Interleukin-10; Interleukin-17; Male; Mice; Mice, Inbred C57BL; Receptors, Antigen, T-Cell, gamma-delta; Spleen; T-Lymphocyte Subsets; Transforming Growth Factor beta; Viremia; West Nile Fever; West Nile virus

Increased activity of IDO, which catalyzes the degradation of Trp into kynurenine (Kyn), is observed during HIV/SIV infection, and it may contribute to the persistence of HIV/SIV by suppressing antiviral T cell responses. We administered the IDO inhibitor 1-methyl-d-tryptophan (d-1mT) for 13 days to SIV-infected rhesus macaques receiving antiretroviral therapy (ART). d-1mT treatment increased the plasma levels of Trp, without reducing the levels of Kyn, suggesting only a partial effect on IDO enzymatic activity. Surprisingly, d-1mT significantly reduced the virus levels in plasma and lymph nodes of ART-treated animals with incomplete responsiveness to ART. In SIV-infected animals that were not receiving ART, d-1mT was ineffective in reducing the plasma viral load and had only a marginal effect on the plasma Kyn/Trp ratio. Increased IDO and TGF-beta mRNA expression in lymph nodes of ART-treated macaques after d-1mT treatment suggested that compensatory counterregulatory mechanisms were activated by d-1mT, which may account for the lack of effect on plasma Kyn. Finally, d-1mT did not interfere with the ART-induced T cell dynamics in lymph nodes (increased frequency of total CD4 T cells, increase of CD8 T cells expressing the antiapoptotic molecule Bcl2, and reduction of regulatory T cells). Thus, d-1mT appeared to synergize with ART in inhibiting viral replication and did not interfere with the beneficial immunologic effects of ART. Further studies are required to elucidate the immunologic or virologic mechanism by which d-1mT inhibited SIV replication in vivo.

Topics: Animals; Anti-Retroviral Agents; Chromatography, High Pressure Liquid; Drug Therapy, Combination; Enzyme Inhibitors; Flow Cytometry; Indoleamine-Pyrrole 2,3,-Dioxygenase; Kynurenine; Lymph Nodes; Macaca mulatta; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Viral; Simian Acquired Immunodeficiency Syndrome; T-Lymphocytes; Transforming Growth Factor beta; Tryptophan; Viremia

When viral infection occurs, this information is transmitted to the brain, and symptoms such as fever and tiredness are induced. One of the causes of these symptoms is the secretion of proinflammatory cytokines in blood and the brain. In this study, the i.p. administration of polyinosinic:polycytidylic acid (poly I:C), a synthetic double-stranded RNA, to rats was used as an infection model. Poly I:C decreased spontaneous motor activity (SMA) 2 h after i.p. administration, and this decrease was maintained thereafter. The concentration of active transforming growth factor-beta (TGF-beta) in cerebrospinal fluid (CSF) increased 1 h after the administration. This increase occurred earlier than those in the concentrations of other proinflammatory cytokines, such as interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), in serum. The intracisternal administration of an anti-TGF-beta antibody partially inhibited fever induced by poly I:C administration; however, this treatment did not affect the decrease in SMA. Furthermore, intracisternal administration of TGF-beta raised the body temperature. These results indicate that TGF-beta in the brain, which was increased by poly I:C administration, is associated with fever but not with a decrease in SMA.

Topics: Animals; Antibodies; Body Temperature; Brain; Fatigue Syndrome, Chronic; Fever; Interferon Inducers; Male; Motor Activity; Poly I-C; Rats; Rats, Sprague-Dawley; Transforming Growth Factor beta; Up-Regulation; Viremia

The loss of CD4(+) T cells and the impairment of CD8(+) T cell function in HIV infection suggest that pharmacological treatment with IL-7 and IL-15, cytokines that increase the homeostatic proliferation of T cells and improve effector function, may be beneficial. However, these cytokines could also have a detrimental effect in HIV-1-infected individuals, because both cytokines increase HIV replication in vitro. We assessed the impact of IL-7 and IL-15 treatment on viral replication and the immunogenicity of live poxvirus vaccines in SIV(mac251)-infected macaques (Macaca mulatta). Neither cytokine augmented the frequency of vaccine-expanded CD4(+) or CD8(+) memory T cells, clonal recruitment to the SIV-specific CD8(+) T cell pool, or CD8(+) T cell function. Vaccination alone transiently decreased the viral set point following antiretroviral therapy suspension. IL-15 induced massive proliferation of CD4(+) effector T cells and abrogated the ability of vaccination to decrease set point viremia. In contrast, IL-7 neither augmented nor decreased the vaccine effect and was associated with a decrease in TGF-beta expression. These results underscore the importance of testing immunomodulatory approaches in vivo to assess potential risks and benefits for HIV-1-infected individuals.

Topics: Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; HIV Infections; HIV-1; Humans; Immunologic Memory; Interleukin-15; Interleukin-7; Macaca mulatta; SAIDS Vaccines; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; Transforming Growth Factor beta; Viremia; Virus Replication

Transforming growth factor (TGF)-beta 1 suppresses the proliferation and cytotoxicity of natural killer (NK) cells, which play critical roles in resolving hepatitis C virus (HCV) infection, especially during the acute phase. We examined 230 anti-HCV antibody-positive subjects for HCV RNA and the -509T/C genotype in the TGF-beta 1 gene promoter. The -509CC genotype and the -509C allele were significantly associated with higher HCV clearance rates (P=.01) and with lower transcriptional activity. The genetic effect remained significant even after adjustment for a history of transfusion. Low TGF- beta 1 producers might have less suppression of NK cells and be more likely to resolve HCV infection.

Topics: Adult; Aged; Aged, 80 and over; Alleles; Female; Genotype; Hepacivirus; Hepatitis C, Chronic; Humans; Male; Middle Aged; Polymorphism, Genetic; Reverse Transcriptase Polymerase Chain Reaction; RNA, Viral; Transforming Growth Factor beta; Transforming Growth Factor beta1; Viremia

T cell activation levels in HIV infection are predictive of AIDS progression. We searched for the immunological correlates of protection against disease progression by studying the early stages of nonpathogenic SIV infection in African green monkeys (SIVagm). The African green monkeys (AGMs) displayed high peak viremias and a transient decline in levels of blood CD4(+) and CD8(+) T cells between days 5 and 17 after infection. A concomitant increase in levels of CD4(+)DR(+), CD8(+)DR(+), and CD8(+)CD28(-) cells was detected. After the third week, T cell activation returned to baseline levels, which suggested a protective downregulation of T cell activation. A very early (24 hours after infection) and strong induction of TGF-beta1 and FoxP3 expression was detected and correlated with increases in levels of CD4(+)CD25(+) and CD8(+)CD25(+) T cells. This was followed by a significant increase in levels of IL-10, whereas IFN-gamma gene upregulation was more transient, and levels of TNF-alpha and MIP-1alpha/beta transcripts did not increase in either blood or tissues. The profiles were significantly different during primary SIV infection in macaques (SIVmac); that is, there was a delayed increase in IL-10 levels accompanied by moderate and persistent increases in TGF-beta levels. Together, our data show that SIVagm infection is associated with an immediate antiinflammatory environment and suggest that TGF-beta may participate in the generation of Tregs, which may prevent an aberrant chronic T cell hyperactivation.

Topics: Acquired Immunodeficiency Syndrome; Animals; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chemokine CCL5; Chlorocebus aethiops; Disease Progression; DNA-Binding Proteins; Humans; Interferon-gamma; Interleukin-10; Lymphocyte Activation; Receptors, CCR1; Receptors, CCR5; Receptors, Chemokine; RNA, Viral; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; T-Lymphocyte Subsets; Transforming Growth Factor beta; Transforming Growth Factor beta1; Viremia