Chronic enteroviral meningoencephalitis in agammaglobulinemia: Case report and literature review

Misbah, Siraj; Spickett, GP; Ryba, P. C. J.; Hockaday, Judith M.; Kroll, J. Simon; Sherwood, Charles H.; Kurtz, J. B.; Moxon, E. Richard; Chapel, Helen

doi:10.1007/bf00918150

Cited by 145 publications

(78 citation statements)

References 19 publications

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“…NI, Not infected; ST2, T1/ST2. Because Abs are essential for viral clearance during enteroviral infection (26,27), we first determined the levels of CVB5-specific Abs in infected WT and T1/ST2 2/2 mice. We found that T1/ ST2 2/2 mice produced more serum anti-CVB5 IgG and IgM than WT mice (Supplemental Fig.…”

Section: Il-33 Is Produced Post Cvb5 Infection and Is Essential For Tmentioning

confidence: 99%

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

Sesti-Costa

Silva

Proença-Modena

et al. 2013

The Journal of Immunology

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Coxsackievirus B (CVB) is a common cause of acute and chronic infectious myocarditis and pancreatitis. Th1 cells producing IFN-γ and TNF-α are important for CVB clearance, but they are also associated with the pathogenesis of inflammatory lesions, suggesting that the modulation of Th1 and Th2 balance is likely important in controlling CVB-induced pancreatitis. We investigated the role of IL-33, which is an important recently discovered cytokine for induction of Th2-associated responses, in experimental CVB5 infection. We found that mice deficient in IL-33R, T1/ST2, significantly developed more severe pancreatitis, had greater weight loss, and contained higher viral load compared with wild-type (WT) mice when infected with CVB5. Conversely, WT mice treated with rIL-33 developed significantly lower viral titers, and pancreatitis was attenuated. Mechanistic studies demonstrated that IL-33 enhances the degranulation and production of IFN-γ and TNF-α by CD8+ T and NK cells, which is associated with viral clearance. Furthermore, IL-33 triggers the production of IL-4 from mast cells, which results in enhanced differentiation of M2 macrophages and regulatory T cells, leading to the attenuation of inflammatory pancreatitis. Adoptively transferred mast cells or M2 macrophages reversed the heightened pancreatitis in the T1/ST2−/− mice. In contrast, inhibition of regulatory T cells exacerbated the disease in WT mice. Together, our findings reveal an unrecognized IL-33/ST2 functional pathway and a key mechanism for CVB5-induced pancreatitis. These data further suggest a novel approach in treating virus-induced pancreatitis, which is a major medical condition with unmet clinical needs.

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Section: Il-33 Is Produced Post Cvb5 Infection and Is Essential For Tmentioning

confidence: 99%

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

Sesti-Costa

Silva

Proença-Modena

et al. 2013

The Journal of Immunology

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“…High-pressure liquid chromatographypurified (Ͼ95% pure) major histocompatibility complex (MHC) class I peptides GP [33][34][35][36][37][38][39][40][41] (KAVYNFATM) and NP 396-404 (FQPQNGQFI) were purchased from Peptidogenic (Livermore, Calif.). Spleen cells (2 ϫ 10 6 per well) from virusinfected mice were stimulated with 10 Ϫ7 M peptide in the presence of 2 g/ of brefeldin A (Sigma, St. Louis, Mo.)…”

Section: Intracellular Cytokine Staining (Iccs)mentioning

confidence: 99%

“…Antibodies are important in eradicating enteroviruses, and agammaglobulinemic humans are susceptible to chronic infections with polioviruses (26), echoviruses (35,38), and coxsackieviruses (16,20). However, T cells also play a role in limiting viral titers (18,55), and antibodies appear to contribute little to the protection induced by a CVB DNA vaccine (19), suggesting that virus-specific memory T cells might be important in vaccine-induced immunity.…”

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confidence: 99%

Using Recombinant Coxsackievirus B3 To Evaluate the Induction and Protective Efficacy of CD8⁺T Cells during Picornavirus Infection

Slifka

Pagarigan

Mena

et al. 2001

J Virol

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Coxsackievirus B3 (CVB3) is a common human pathogen that has been associated with serious diseases including myocarditis and pancreatitis. To better understand the effect of cytotoxic T-lymphocyte (CTL) responses in controlling CVB3 infection, we have inserted well-characterized CTL epitopes into the CVB3 genome. Constructs were made by placing the epitope of interest upstream of the open reading frame encoding the CVB3 polyprotein, separated by a poly-glycine linker and an artificial 3C pro /3CD pro cleavage site. This strategy results in the foreign protein being translated at the amino-terminus of the viral polyprotein, from which it is cleaved prior to viral assembly. In this study, we cloned major histocompatibility complex class I-restricted CTL epitopes from lymphocytic choriomeningitis virus (LCMV) into recombinant CVB3 (rCVB3). In vitro, rCVB3 growth kinetics showed a 1-to 2-h lag period before exponential growth was initiated, and peak titers were ϳ1 log unit lower than for wild-type virus. rCVB3 replicated to high titers in vivo and caused severe pancreatitis but minimal myocarditis. Despite the high virus titers, rCVB3 infection of naive mice failed to induce a strong CD8 ؉ T-cell response to the encoded epitope; this has implications for the proposed role of "cross-priming" during virus infection and for the utility of recombinant picornaviruses as vaccine vectors. In contrast, rCVB3 infection of LCMV-immune mice resulted in direct ex vivo cytotoxic activity against target cells coated with the epitope peptide, demonstrating that the rCVB3-encoded LCMV-specific epitope was expressed and presented in vivo. The preexisting CD8 ؉ memory T cells could limit rCVB replication; compared to naive mice, infection of LCMV-immune mice with rCVB3 resulted in ϳ50-fold-lower virus titers in the heart and ϳ6-fold-lower virus titers in the pancreas. Although the inserted CTL epitope was retained by rCVB3 through several passages in tissue culture, it was lost in an organ-specific manner in vivo; a substantial proportion of viruses from the pancreas retained the insert, compared to only 0 to 1.8% of myocardial viruses. Together, these results show that expression of heterologous viral proteins by recombinant CVB3 provides a useful model for determining the mechanisms underlying the immune response to this viral pathogen.Coxsackieviruses are members of the family Picornaviridae and lie in the Enterovirus genus, together with polioviruses, echoviruses, and unclassified enteroviruses. Coxsackieviruses are classified, according their pathogenicity in newborn mice, into groups A and B, which comprise 24 and 6 serotypes, respectively. Type B coxsackieviruses (CVB) are common human pathogens and have been implicated in acute and chronic myocarditis; there is a strong correlation between prior CVB infection and dilated cardiomyopathy, which can be effectively treated only by heart transplantation (47). In addition to cardiovascular disease, CVB has been associated with hepatitis, encephalitis, and pancreatitis, and CVB4 inf...

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“…and with virus being cleared by the adaptive immune response (17). However, enterovirus infections can persist under conditions of immunodeficiency (48,51,65,71). Infectious enteroviruses are frequently isolated from pediatric cases of human myocarditis, but isolation from adult cases of the disease has been exceedingly rare (34,62,88), perhaps because pediatric cases may be more likely to be diagnosed during the acute infection.…”

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confidence: 99%

5′-Terminal Deletions Occur in Coxsackievirus B3 during Replication in Murine Hearts and Cardiac Myocyte Cultures and Correlate with Encapsidation of Negative-Strand Viral RNA

Kim

Tracy

Tapprich

et al. 2005

J Virol

142

251

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Adult human enteroviral heart disease is often associated with the detection of enteroviral RNA in cardiac muscle tissue in the absence of infectious virus. Passage of coxsackievirus B3 (CVB3) in adult murine cardiomyocytes produced CVB3 that was noncytolytic in HeLa cells. Detectable but noncytopathic CVB3 was also isolated from hearts of mice inoculated with CVB3. Sequence analysis revealed five classes of CVB3 genomes with 5 termini containing 7, 12, 17, 30, and 49 nucleotide deletions. Structural changes (assayed by chemical modification) in cloned, terminally deleted 5-nontranslated regions were confined to the cloverleaf domain and localized within the region of the deletion, leaving key functional elements of the RNA intact. Transfection of CVB3 cDNA clones with the 5-terminal deletions into HeLa cells generated noncytolytic virus (CVB3/TD) which was neutralized by anti-CVB3 serum. Encapsidated negative-strand viral RNA was detected using CsCl-purified CVB3/TD virions, although no negative-strand virion RNA was detected in similarly treated parental CVB3 virions. The viral protein VPg was detected on CVB3/TD virion RNA molecules which terminate in 5 CG or 5 AG. Detection of viral RNA in mouse hearts from 1 week to over 5 months postinoculation with CVB3/TD demonstrated that CVB3/TD virus strains replicate and persist in vivo. These studies describe a naturally occurring genomic alteration to an enteroviral genome associated with long-term viral persistence.The six serotypes of the group B coxsackieviruses (CVB1-6) are enteroviruses (Picornaviridae, species HEV-B) (53). The CVB genome is a single-stranded RNA molecule, 7,400 nucleotides (nt) in length, that is encapsidated within an icosahedral shell (74). The 11 viral proteins (83) are encoded by a single open reading frame which is flanked on the 5Ј and 3Ј termini by nontranslated regions (NTRs) (20). The CVB induce numerous human illnesses, including inflammatory heart disease, pancreatitis, and aseptic meningitis and may also trigger the onset of type 1 diabetes (5,31,72,81,82). The CVB were recognized as causes of human heart disease shortly after their description early in the 1950s (26, 27) and remain the enteroviruses most commonly associated with human cardiomyopathies on the grounds of isolation and serology (5,6,34,62,88). Meta-analysis shows an association between enteroviruses and myocarditis in 23% of cases (7), although this association is more variable in cases of dilated cardiomyopathy, a serious disease that often leads to a failing heart (61). Mouse models of CVB-induced pancreatitis (94, 110), myocarditis (45,52,110), myositis (104, 105), and rapid-onset type 1 diabetes (31) which facilitate the study of these diseases have been developed.Enterovirus infections are generally considered to be acute events, with symptoms and virus titers peaking within a few days postinoculation (p.i.) and with virus being cleared by the adaptive immune response (17). However, enterovirus infections can persist under conditions of immunodeficiency (48,51,...

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Chronic enteroviral meningoencephalitis in agammaglobulinemia: Case report and literature review

Cited by 145 publications

References 19 publications

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

Using Recombinant Coxsackievirus B3 To Evaluate the Induction and Protective Efficacy of CD8⁺T Cells during Picornavirus Infection

5′-Terminal Deletions Occur in Coxsackievirus B3 during Replication in Murine Hearts and Cardiac Myocyte Cultures and Correlate with Encapsidation of Negative-Strand Viral RNA

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Chronic enteroviral meningoencephalitis in agammaglobulinemia: Case report and literature review

Cited by 145 publications

References 19 publications

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

The IL-33/ST2 Pathway Controls Coxsackievirus B5–Induced Experimental Pancreatitis

Using Recombinant Coxsackievirus B3 To Evaluate the Induction and Protective Efficacy of CD8+T Cells during Picornavirus Infection

5′-Terminal Deletions Occur in Coxsackievirus B3 during Replication in Murine Hearts and Cardiac Myocyte Cultures and Correlate with Encapsidation of Negative-Strand Viral RNA

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Using Recombinant Coxsackievirus B3 To Evaluate the Induction and Protective Efficacy of CD8⁺T Cells during Picornavirus Infection