Rotavirus Infection Alters Peripheral T-Cell Homeostasis in Children with Acute Diarrhea

Abstract

The patterns of gene expression and the phenotypes of lymphocytes in peripheral blood mononuclear cells (PBMC) from children with diarrhea caused by rotavirus and healthy children were compared by using DNA microarray, quantitative PCR, and flow cytometry. We observed increased expression of a number of genes encoding proinflammatory cytokines and interferon or interferon-stimulated proteins and demonstrated activation of some genes involved in the differentiation, maturation, activation, and survival of B lymphocytes in PBMC of patients with rotavirus infection. In contrast, we observed a consistent pattern of lower mRNA levels for an array of genes involved in the various stages of T-cell development and demonstrated a reduction in total lymphocyte populations and in the proportions of CD4 and CD8 T lymphocytes from PBMC of patients. This decreased frequency of T lymphocytes was transient, since the proportions of T lymphocytes recovered to almost normal levels in convalescent-phase PBMC from most patients. Finally, rotavirus infection induced the activation and expression of the early activation markers CD83 and CD69 on a fraction of CD19 B cells and the remaining CD4 and CD8 T lymphocytes in acute-phase PBMC of patients; the expression of CD83 continued to be elevated and was predominantly exhibited on CD4 T lymphocytes in convalescent-phase PBMC. On the basis of these findings at the molecular, phenotypic, and physiologic levels in acute-phase PBMC, we conclude that rotavirus infection induces robust proinflammatory and antiviral responses and B-cell activation but alters peripheral T-cell homeostasis in children.

Rotavirus Differentially Infects and Polyclonally Stimulates Human B Cells Depending on Their Differentiation State and Tissue of Origin

“…In agreement with previous reports of RV-infected splenocytes from mice and PBMC from children with acute RV- induced gastroenteritis (6,70), RV induced the CD69 expression of a significant fraction of CBC when cells were infected as a component of whole PMBC, but there was low or no activation and ASC differentiation observed when purified CBC or IBC were infected (Fig. 4).…”

Rotavirus NSP4 Triggers Secretion of Proinflammatory Cytokines from Macrophages via Toll-Like Receptor 2

“…Elevated levels of inflammatory cytokines correlate directly with the severity and frequency of diarrheal episodes during the acute phase of rotavirus infection in naturally infected children (33,34) and are also observed in experimentally infected gnotobiotic pigs (35,36). Therefore, the observations reported here are consistent with markers of systemic inflammation observed during rotavirus infection in vivo.…”

Virus-specific intestinal IFN-γ producing T cell responses induced by human rotavirus infection and vaccines are correlated with protection against rotavirus diarrhea in gnotobiotic pigs

“…The frequencies of blood CD4+ and CD8+ T cells were reduced or significantly reduced in the VirHRV infected pigs compared to mock-inoculated control pigs at PID28. A recent study of children with acute rotavirus diarrhea also reported moderate to severe reduction in the frequencies of CD4+ and CD8+ T cells from peripheral blood [53]. The reduction in frequency of T cells in children was only detected in the acute-phase blood samples.…”

“…This difference between rotavirus infected Gn pigs and children may be due in part to the Gn status of pigs that lack of commensal microflora or environmental antigen stimulation may have delayed the recovery from the VirHRV-induced T cell lymphopenia. The mechanism for the rotavirus-induced T cell lymphopenia in pigs and children are unclear and requires further studies [53].…”