Natural antibodies (Abs) can target host glycans on the surface of pathogens. We studied the evolution of glycan-reactive B cells of rhesus macaques and humans using glycosylated HIV-1 envelope (Env) as a model antigen. 2G12 is a broadly neutralizing Ab (bnAb) that targets a conserved glycan patch on Env of geographically diverse HIV-1 strains using a unique heavy-chain (VH) domain-swapped architecture that results in fragment antigen-binding (Fab) dimerization. Here, we describe HIV-1 Env Fab-dimerized glycan (FDG)-reactive bnAbs without VH-swapped domains from simian-human immunodeficiency virus (SHIV)-infected macaques. FDG Abs also recognized cell-surface glycans on diverse pathogens, including yeast and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike. FDG precursors were expanded by glycan-bearing immunogens in macaques and were abundant in HIV-1-naive humans. Moreover, FDG precursors were predominately mutated IgM+IgD+CD27+, thus suggesting that they originated from a pool of antigen-experienced IgM+ or marginal zone B cells.
- Klíčová slova
- FDG Abs, Fab dimerization, HIV-1 Env glycans, IgM-memory B cells, SARS-CoV-2 spike glycans, glycan-dependent Ab binding, marginal zone B cells, natural Abs,
- MeSH
- B-lymfocyty imunologie MeSH
- COVID-19 imunologie MeSH
- dimerizace MeSH
- epitopy imunologie MeSH
- genové produkty env - virus lidské imunodeficience chemie genetika imunologie MeSH
- glykoprotein S, koronavirus imunologie MeSH
- glykosylace MeSH
- HIV infekce imunologie MeSH
- HIV protilátky imunologie MeSH
- HIV-1 imunologie MeSH
- imunoglobuliny - Fab fragmenty chemie imunologie MeSH
- lidé MeSH
- Macaca mulatta MeSH
- neutralizující protilátky imunologie MeSH
- polysacharidy chemie imunologie MeSH
- receptory antigenů B-buněk chemie MeSH
- SARS-CoV-2 imunologie MeSH
- široce neutralizující protilátky imunologie MeSH
- vakcíny imunologie MeSH
- virus opičí imunodeficience genetika imunologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Názvy látek
- epitopy MeSH
- genové produkty env - virus lidské imunodeficience MeSH
- glykoprotein S, koronavirus MeSH
- HIV protilátky MeSH
- imunoglobuliny - Fab fragmenty MeSH
- neutralizující protilátky MeSH
- polysacharidy MeSH
- receptory antigenů B-buněk MeSH
- široce neutralizující protilátky MeSH
- spike protein, SARS-CoV-2 MeSH Prohlížeč
- vakcíny MeSH
Increased CD4+ T cell apoptosis and activation induced cell death (AICD) as a result of HIV infection in humans and SIV infection in Rhesus macaques (RM) is indicative of disease. Some non-human primate species naturally infected by SIV, such as African sooty mangabeys (SM), do not succumb to SIV despite high viral loads. Previously, we showed that mRNA levels of GSK-3β a kinase involved in T cell signaling, are significantly decreased in SIV+ RM compared to SIV+ SM. The current study confirms that expression of GSK-3β is decreased at the protein level in SIV+ RM. In addition, CD4+ T cells from SIV+ RM, but not other animals show an increase in both total Akt, a kinase directly interacting with GSK-3β and p-AktThr308 in response to stimulation via CD3/CD28, which is associated with an increase in apoptosis. Furthermore, the differences between the uninfected and pathogenically or non-pathogenically infected animals are not only species specific, but also T cell subset specific and that these trends correlate with AICD. This is one of few studies indicating the activity of Akt can be specific to only one phosphorylation site and may be linked to the differences in AICD and resistance to the lentivirus induced disease.
- Klíčová slova
- T cells - AIDS - Nonhuman primate - Akt - intracellular signaling.,
- MeSH
- AIDS opičí * imunologie metabolismus MeSH
- CD4-pozitivní T-lymfocyty * imunologie metabolismus MeSH
- fosforylace imunologie MeSH
- Macaca mulatta MeSH
- protoonkogenní proteiny c-akt * imunologie metabolismus MeSH
- virus opičí imunodeficience imunologie MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Názvy látek
- protoonkogenní proteiny c-akt * MeSH
Microsporidia cause opportunistic infections in AIDS patients and commonly infect laboratory animals, as well. Euthymic C57B1/6 mice experimentally infected with intraperitoneal injections of 1 x 10(6) Encephalitozoon cuniculi Levaditi, Nicolau et Schoen, 1923, Encephalitozoon hellem Didier et al., 1991, or Nosema corneum Shadduck et al., 1990 displayed no clinical signs of disease. Athymic mice, however, developed ascites and died 8-16 days after inoculation with N. corneum, 21-25 days after inoculation with E. cuniculi, and 34-37 days after inoculation with E. hellem. All athymic mice displayed hepatomegaly, dilated intestine and accumulation of ascites fluid. Granulomatous lesions are primarily located in the liver, lung, pancreas, spleen, and on serosal surfaces of abdominal organs. The murine microsporidiosis model also was used to examine immune response that inhibit microsporidia growth in vitro. Recombinant murine interferon-gamma (mIFN-gamma, 100 mu/ml) alone or in combination with lipopolysaccharide (LPS; 10 ng/ml) could activate thioglycollate-induced peritoneal murine macrophages to destroy E. cuniculi. The production of the nitrogen intermediate, NO2-, correlated with parasite destruction. Inhibition of NO2- generation by addition of the L-arginine analogue, NG-monomethyl L-arginine (NMMA), inhibited microsporidia killing, as well. Since microsporidiosis is becoming an important opportunistic infection in AIDS patients, a microsporidiosis model is being developed using SIV/DeltaB670-infected rhesus macaque monkeys (Macaca mulatta). SIV-infected immunocompetent monkeys given E. cuniculi or E. hellem per os developed specific antibodies, and microsporidia could be detected sporadically by calcofluor or antibody fluorescence staining of stool and urine sediment smears. As immunodeficiency progressed, monkeys developed diarrhoea, cachexia, and anorexia, and organisms were detected in urine and stool with greater frequency. Immunodeficient SIV-infected monkeys died approximately 27 days after receiving E. hellem by intravenous inoculation, and approximately 110 days after receiving E. hellem per os. Lesions typical for SIV-infection were observed in both groups of monkeys and microsporidia were detected in kidney and liver of the intravenously-injected monkeys. The murine microsporidiosis model provides an efficient means for studying protective immune responses to microsporidiosis, and may prove useful for screening immunological and chemotherapeutic agents. The pathogenesis of Encephalitozoon microsporidiosis in SIV-infected monkeys appears to parallel encephalitozoonosis in AIDS patients, suggesting that simian microsporidiosis may provide a useful model for evaluating diagnostic methods and therapeutic strategies during various stages of progressing immunodeficiency.
- MeSH
- AIDS opičí imunologie mikrobiologie MeSH
- arginin analogy a deriváty farmakologie MeSH
- cytokiny farmakologie MeSH
- Encephalitozoon imunologie MeSH
- encephalitozoonóza imunologie parazitologie MeSH
- imunokompetence MeSH
- inbrední kmeny myší MeSH
- interferon gama farmakologie MeSH
- lipopolysacharidy farmakologie MeSH
- Macaca mulatta MeSH
- mikrosporidióza imunologie parazitologie MeSH
- modely nemocí na zvířatech MeSH
- myši MeSH
- Nosema imunologie MeSH
- omega-N-methylarginin MeSH
- oportunní infekce imunologie MeSH
- oxid dusnatý antagonisté a inhibitory metabolismus MeSH
- peritoneální makrofágy účinky léků metabolismus parazitologie MeSH
- protilátky protozoální krev MeSH
- virus opičí imunodeficience imunologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
- srovnávací studie MeSH
- Názvy látek
- arginin MeSH
- cytokiny MeSH
- interferon gama MeSH
- lipopolysacharidy MeSH
- omega-N-methylarginin MeSH
- oxid dusnatý MeSH
- protilátky protozoální MeSH
