[PMC free article] [PubMed] [Google Scholar]Slifka MK, Pagarigan R, Mena I, Feuer R, Whitton JL

[PMC free article] [PubMed] [Google Scholar]Slifka MK, Pagarigan R, Mena I, Feuer R, Whitton JL. exploit autophagy to maximize viral replication and assist in unconventional release from target cells. In this article, we review recent progress in clarifying virus replication and dissemination within the host cell, identifying determinants of tropism, and defining strategies utilized by the virus to evade the host immune response. Also, we will highlight unanswered questions and provide future perspectives regarding the potential mechanisms of CV pathogenesis. Introduction Enteroviruses (EVs) are widely distributed in nature and frequently cause heart and KI67 antibody central nervous system (CNS) diseases (Whitton, Cornell et al., 2005) (Muir & van Loon, 1997). EVs are members of the Picornaviridae family which include notable members such as foot-and-mouth disease virus, poliovirus (PV), rhinovirus and hepatitis A. Some EVs, particularly enterovirus-71 (EV71) in Asia, are considered to be serious emerging CNS pathogens (Shih, Stollar gamma-secretase modulator 3 et al., 2011). The EV genus includes an important member, coxsackievirus (CV), which cause severe morbidity and mortality in the newborn and young host (Tebruegge & Curtis, 2009) (Romero, 2008). These viruses have a small, positive-sense single stranded RNA genome, and infection occurs primarily through the fecal-oral gamma-secretase modulator 3 route (Whitton, Cornell et al., 2005) (Feng, Langereis et al., 2014b). Approximately 15 million diagnosed cases of EV infections occurred gamma-secretase modulator 3 in the US in 1996, revealing that EV remains a substantial problematic viral infection (Sawyer, 2002). The original classification of EVs included the four groups: Coxsackie A viruses, Coxsackie B (CVB) viruses, ECHO (and childhood infection is under-recognized but carries long-term consequences whereby intellectual and cognitive abilities of the patient might be compromised (Chiriboga-Klein, Oberfield et al., 1989) (Euscher, Davis et al., 2001;Chang, Huang et al., 2007) (Chamberlain, Christie et al., 1983). A relatively common pediatric virus, CV typically causes mild infections ranging from subclinical to flu-like symptoms and mild gastroenteritis (Weller, Simpson et al., 1989). CV has been shown to infect the heart, pancreas, and CNS (Arnesjo, Eden et al., 1976) (Rhoades, Tabor-Godwin et al., 2011). In rare cases CVs cause severe systemic inflammatory diseases such meningo-encephalitis, pancreatitis, and myocarditis, all of which can be fatal or result in lasting organ dysfunction, including dilated cardiomyopathy and encephalomyelitis (David, Baleriaux et al., 1993) (Hyypia, Kallajoki et al., 1993). The remarkable distribution of CV infections can be appreciated by the high seroprevalence in many countries around the world. In one study, IgG antibodies against CV were detected in 6.7 to 21.6% of individuals throughout various regions of Greece (Mavrouli, Spanakis et al., 2007). An analysis of a French-Canadian population in Montreal showed a seroprevalence as high as 60-80% for some strains of CV (Payment P., 1991). In a region of China, the seroprevalence for a single serotype of CV was shown to be greater than 50% in groups aged 15 years or more (Tao, Li et al., 2013). The wide distribution of CV, their genetic variability, and ability to persist in the human host make it challenging for epidemiologists to link previous viral infection and subsequent pathology, suggesting a potential role for these viruses in chronic human idiopathies (Victoria, Kapoor et al., 2009) in addition to recognized illnesses. Vaccine design against CVs and EVs gamma-secretase modulator 3 remain challenging for a number of reasons which include their remarkable genetic variability and inconsistent pathology in humans. Spontaneous abortions, fetal myocarditis, and neurodevelopmental delays in the newborn remain serious outcomes if CV infection occurs during pregnancy (Ornoy & Tenenbaum, 2006) (Euscher, Davis et al., 2001). Infants infected with CV have a higher likelihood of developing myocarditis, meningitis and encephalitis; and the mortality rate may be as high as 10%. Also, many chronic diseases may be the end result of a previous CV infection. These chronic diseases include chronic myocarditis (Chapman & Kim, 2008), schizophrenia (Rantakallio, Jones et al., 1997), encephalitis lethargica (Cree, Bernardini et al., 2003), and amyotrophic lateral sclerosis (Woodall, Riding et al., 1994) (Woodall & Graham, 2004). The molecular mechanisms determining the tropism of CVs and their ability to persist in the host remain unclear. The lasting consequences of CV infection upon surviving individuals remain largely unknown despite clear dangers associated with infection and the cytolytic nature of the virus. Many publications have suggested a link between early CV infection and insulin-dependent diabetes (IDDM) (Laitinen, Honkanen et al., 2014) (Jaidane & Hober, 2008) (Christen, Bender et al., 2012), although additional data is needed to support these correlative studies. In addition, a mouse model has shown the development of insulin-dependent diabetes (IDDM) to be associated with CV-induced pancreatitis and replication efficiency (Drescher, Kono et al., 2004), although the factors determining viral tropism and mechanism of disease are not well understood (Tracy, Drescher et al., 2011) (Kanno,.