Lymphocyte apoptosis in acute respiratory syncytial virus bronchiolitis

429

478

Human respiratory syncytial virus (RSV) was first isolated in 1956 from a laboratory chimpanzee with upper respiratory tract disease (for general reviews, see references 21, 57, 102, and 145). RSV was quickly determined to be of human origin and was shown to be the leading worldwide viral agent of serious pediatric respiratory tract disease. In a 13-year prospective study of infants and children in the United States, RSV was detected in 43%, 25%, 11%, and 10% of pediatric hospitalizations for bronchiolitis, pneumonia, bronchitis, and croup, respectively (110). Approximately two-thirds of infants are infected with RSV during the first year of life, and 90% have been infected one or more times by 2 years of age. The rate of hospitalization for primary infection is approximately 0.5% but can vary by situation and ethnic group and can be as high as 25% (77).RSV also is a significant cause of morbidity and mortality in the elderly, with an impact approaching that of nonpandemic influenza virus (39). RSV readily infects severely immunocompromised individuals, most notably allogeneic bone marrow transplant recipients, causing high mortality. RSV also makes a substantial contribution to upper respiratory tract disease in individuals of all ages (59,65 Although RSV has a single serotype, reinfection can occur throughout life. RSV in yearly winter/early spring epidemics in temperate regions; elsewhere, the timing of RSV activity can vary widely with the locale. The RSV reservoir in the offseason is unknown. Strains circulate quickly around the earth (150). Neither a vaccine nor an effective antiviral therapy is available, although there is active research in both areas (23,78,138). However, infants at high risk for serious disease can receive passive immunoprophylaxis during the epidemic season by a monthly injection of a commercial RSV-neutralizing monoclonal antibody, palivizumab (Synagis), which provides a 55% reduction in RSV-associated hospitalization (17). THE VIRUSRSV (family Paramyxoviridae, order Mononegavirales) is an enveloped virus with a single-stranded negative-sense RNA genome of 15.2 kb (21). There are animal versions of RSV, including bovine RSV (BRSV) and pneumonia virus of mice (PVM), suggesting that species jumping occurred during the evolution of these viruses. However, there is no animal reservoir for human RSV.Efficient infection by RSV of established cell lines in vitro involves binding to cell-surface glycosaminoglycans (62). However, it is not known how closely this binding models attachment in vivo or whether it is an initial interaction that is followed by a second, higher-affinity step that remains to be identified. The nucleocapsid gains entry to the cytoplasm by membrane fusion; surprisingly, this may involve clathrin-mediated endocytosis rather than surface fusion typical of paramyxoviruses (85). Viral gene expression and RNA replication occur in the cytoplasm, and virions acquire a lipid envelope by budding through the plasmid membrane (Fig. 1). Virions are pleomorphic and include spheres ...

Section: Protective and Pathogenic Features Of The Host Responsementioning

confidence: 89%

Viral and Host Factors in Human Respiratory Syncytial Virus Pathogenesis

Collins¹,

Graham

2008

429

478

“…RSV has been noted to affect a number of immune responses, including impairment of lymphoproliferation (69), decreased CD8 ϩ T cell response by human peripheral blood mononuclear cells (PBMCs) when infected in vitro (70), increased apoptosis of peripheral lymphocytes during acute infection in infants (71), increase in IL-10 and regulatory T cells in lungs of infected mice (72)(73)(74)(75), and altered dendritic cell stimulation of T cells in mice (76,77) and in human PBMCs or cord blood mononuclear cells in vitro (78)(79)(80). The G protein specifically has been associated with suppressing a number of immune responses, including induction of Toll-like receptor 3 (TLR3) or 4, IFN-␤ (81), proinflammatory responses of lung epithelial cells (82), lymphoproliferation (83), and activation of dendritic cells (84,85).…”

Section: Discussionmentioning

confidence: 99%

Prophylaxis with a Respiratory Syncytial Virus (RSV) Anti-G Protein Monoclonal Antibody Shifts the Adaptive Immune Response to RSV rA2-line19F Infection from Th2 to Th1 in BALB/c Mice

Boyoglu-Barnum

Chirkova

Todd

et al. 2014

Respiratory syncytial virus (RSV) is IMPORTANCEThe data in this report suggest that the RSV G protein not only contributes to disease but also dampens the host immune response to infection. Both effects of G likely contribute to difficulties in achieving an effective vaccine. The ability of MAb 131-2G to block these effects of G suggests that inducing antibodies similar to 131-2G should prevent disease and enhance the adaptive immune response with later RSV infection. The fact that 131-2G binds to the 13-amino-acid region conserved among all strains and that flanking sequences are conserved within group A or group B strains simplifies the task of developing a vaccine to induce 131-2G-like antibodies. If our findings in mice apply to humans, then including the 131-2G binding region of G in a vaccine should improve its safety and efficacy.

“…We and others have shown that both human and bovine strains of RSV activate apoptosis in cognate host cells at late stages of infection (4,14,30,34,37) and also sensitize the cells to extrinsic apoptotic agents (24). In mammalian cells, the AKT pathway generally promotes a prosurvival, antiapoptotic state (16,49).…”

mentioning

confidence: 99%

Nonstructural Proteins of Respiratory Syncytial Virus Suppress Premature Apoptosis by an NF-κB-Dependent, Interferon-Independent Mechanism and Facilitate Virus Growth

Bitko

Shulyayeva

Mazumder

et al. 2007

152

112

The two nonstructural (NS) proteins NS1 and NS2 of respiratory syncytial virus (RSV) are abundantly expressed in the infected cell but are not packaged in mature progeny virions. We found that both proteins were expressed early in infection, whereas the infected cells underwent apoptosis much later. Coincident with NS protein expression, a number of cellular antiapoptotic factors were expressed or activated at early stages, which included NF-B and phosphorylated forms of protein kinases AKT, phosphoinositide-dependent protein kinase, and glycogen synthase kinase. Using specific short interfering RNAs (siRNAs), we achieved significant knockdown of one or both NS proteins in the infected cell, which resulted in abrogation of the antiapoptotic functions and led to early apoptosis. NS-dependent suppression of apoptosis was observed in Vero cells that are naturally devoid of type I interferons (IFN). The siRNA-based results were confirmed by the use of NS-deleted RSV mutants. Early activation of epidermal growth factor receptor (EGFR) in the RSV-infected cell did not require NS proteins. Premature apoptosis triggered by the loss of NS or by apoptosis-promoting drugs caused a severe reduction of RSV growth. Finally, recombinantly expressed NS1 and NS2, individually and together, reduced apoptosis by tumor necrosis factor alpha, suggesting an intrinsic antiapoptotic property of both. We conclude that the early-expressed nonstructural proteins of RSV boost viral replication by delaying the apoptosis of the infected cell via a novel IFN-and EGFR-independent pathway.The respiratory syncytial virus (RSV), a member of the Pneumovirus genus within the family Paramyxoviridae, is a ubiquitous cause of severe respiratory infection with a worldwide and seasonal distribution (26). It is the most common cause of lower respiratory tract infection in infants and senior citizens and is life-threatening in immunocompromised individuals such as premature babies, organ recipients, and AIDS patients. Large-scale surveillance studies have estimated that tens of millions of people in the United States alone suffer from RSV infection every winter. Despite intense research for more than two decades, there is no reliable treatment or preventive medicine against RSV.The RSV genome is a 15-kb-long, single-stranded, negativesense RNA, transcribed and replicated by the virally encoded RNA-dependent RNA polymerase (RdRP), minimally composed of the large protein (L) and the phosphoprotein (P). The overall strategy of RSV gene expression is common to all members of the negative-strand RNA virus superfamily (2, 28). The initial rounds of transcription, known as "primary" transcription, are carried out by the RdRP activity associated with the incoming viral genome. The transcribed mRNAs are translated into de novo viral proteins including more RdRP, which boosts new rounds of viral gene expression. Perhaps the most unique feature that distinguishes the Pneumovirus genus from the rest of the Paramyxoviridae family is the presence of two nonstructural (...