Exogenous Interleukin-12 Protects against Lethal Infection with Coxsackievirus B4

Potvin, Daniel M.; Metzger, Dennis W.; Lee, William T.; Collins, Doris N.; Ramsingh, Arlene I.

doi:10.1128/jvi.77.15.8272-8279.2003

Cited by 27 publications

(23 citation statements)

References 34 publications

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“…If true, then a prediction of the model is that modulation of either the angiogenic or immune response during CVB4-V infection would be beneficial. We have recently shown that immune modulation via cytokine (interleukin-12) administration protects the exocrine pancreas and prevents morbidity and mortality during CVB4-V infection (32). Since the inflammatory milieu induced by CVB4 may influence disease progression, future studies will examine global gene expression early in the infection process to identify candidate genes that influence the outcome of infection.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Progression or Resolution of Coxsackievirus B4-Induced Pancreatitis: a Genomic Analysis

Ostrowski¹,

Reilly

Collins

et al. 2004

J Virol

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Group B coxsackieviruses are associated with chronic inflammatory diseases of the pancreas, heart, and central nervous system. Chronic pancreatitis, which can develop from acute pancreatitis, is considered a premalignant disorder because it is a major risk factor for pancreatic cancer. To explore the genetic events underlying the progression of acute to chronic disease, a comparative analysis of global gene expression during coxsackievirus B4-induced acute and chronic pancreatitis was undertaken. A key feature of acute pancreatitis that resolved was tissue regeneration, which was accompanied by increased expression of genes involved in cell growth, inhibition of apoptosis, and embryogenesis and by increased division of acinar cells. Acute pancreatitis that progressed to chronic pancreatitis was characterized by lack of tissue repair, and the expression map highlighted genes involved in apoptosis, acinoductular metaplasia, remodeling of the extracellular matrix, and fibrosis. Furthermore, immune responses appeared skewed toward development of alternatively activated (M2) macrophages and T helper 2 (Th2) cells during disease that resolved and toward classically activated (M1) macrophages and Th1 cells during disease that progressed. Our hypothesis is that growth and differentiation signals coupled with the M2/Th2 milieu favor acinar cell proliferation, while diminished growth signals and the M1/Th1 milieu favor apoptosis of acinar cells and remodeling/proliferation of the extracellular matrix, resulting in fibrosis.The group B coxsackieviruses are associated with chronic inflammatory diseases of the pancreas (insulin-dependent diabetes mellitus and idiopathic chronic pancreatitis), heart (dilated cardiomyopathy), and central nervous system (12). Efforts to elucidate the mechanisms by which these viruses cause disease have focused on identifying the molecular determinants of viral virulence and understanding the immune response to infection. The molecular determinants of viral virulence for the group B coxsackieviruses are distinct, suggesting that these viruses induce disease via diverse mechanisms. For coxsackievirus B3 (CVB3), determinants of attenuation and virulence have been identified in the 5Ј untranslated region (42) and in VP2 (21). For CVB4, Thr-129 of VP1 is a major determinant of virulence (11). The precise mechanism by which the viral molecular determinants cause tissue injury is not clear. During coxsackievirus B infection, both virus-induced cytopathology and immunopathological mechanisms have been implicated in mediating tissue injury (12, 36).Our mouse model uses two serologically indistinguishable variants of the CVB4 serotype that cause acute and chronic pancreatitis reminiscent of clinical disease. The CVB4-P variant induces a transient, acute disease which shares pathological features (edema and inflammation) (34) with acute, interstitial pancreatitis in humans (9). The CVB4-V variant induces a severe, acute disease which progresses to chronic pancreatitis. CVB4-V-induced chronic pancreatitis ...

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Section: Discussionmentioning

confidence: 99%

“…For CVB4-V infections, a dose of 50 PFU was used. Because CVB4-V-infected mice develop exocrine pancreatic insufficiency (35), mice were given supplements of pancreatic enzymes (1 mg of pancreatin per ml) and sucrose (10%) in their drinking water to minimize morbidity (32). Mice were allowed to eat and drink ad libitum.…”

Section: Methodsmentioning

confidence: 99%

Progression or Resolution of Coxsackievirus B4-Induced Pancreatitis: a Genomic Analysis

Ostrowski¹,

Reilly

Collins

et al. 2004

J Virol

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“…Results from preliminary experiments indicated that 0.5 g of IL-12 was optimal for protective efficacy, and no toxicity has been observed with this i.n. dose of IL-12 (15,21). Control mice received vehicle alone 24 h before infection.…”

Section: Methodsmentioning

confidence: 99%

Intranasal Interleukin-12 Treatment for Protection against Respiratory Infection with theFrancisella tularensisLive Vaccine Strain

et al. 2005

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Francisella tularensis is a gram-negative intracellular bacterium that can induce lethal respiratory infection in humans and rodents. However, little is known about the role of innate or adaptive immunity in protection from respiratory tularemia. In the present study, the role of interleukin-12 (IL-12) in inducing protective immunity in the lungs against intranasal infection of mice with the live vaccine strain (LVS) of F. tularensis was investigated. It was found that gamma interferon (IFN-␥) and IL-12 were strictly required for protection, since mice deficient in IFN-␥, IL-12 p35, or IL-12 p40 all succumbed to LVS doses that were sublethal for wild-type mice. Furthermore, exogenous IL-12 treatment 24 h before intranasal infection with a lethal dose of LVS (10,000 CFU) significantly decreased bacterial loads in the lungs, livers, and spleens of wild-type BALB/c and C57BL/6 mice and allowed the animals to survive infection; such protection was not observed in IFN-␥-deficient mice. The resistance induced by IL-12 to LVS infection was still observed in NK cell-deficient beige mice but not in CD8 ؊/؊ mice. These results demonstrate that exogenous IL-12 delivered intranasally can prevent respiratory tularemia through a mechanism that is at least partially dependent upon the expression of IFN-␥ and CD8 T cells.

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“…Two days after V-virus infection, there was a trend of elevated serum amylase and lipase in K8-null and K18-null mice compared to their respective WT and heterozygous counterparts ( Table 2). The increased resistance of WT, heterozygous and K18-null mice to lethality by CVB4-V compared to published data in WT mice 21 could be due to differences in genetic background or age. Collectively, these data demonstrate that K8-null, but not K18-null, renders mice more susceptible to death by CVB4-V virus-induced pancreatitis.…”

Section: Virus Infectionmentioning

confidence: 77%

“…For example, IL-4-null mice survive CVB4-V infection, and normal mice administered IL-12 are protected from CVB4-V infection possibly due to increased IFNγ levels. 21,40 During CVB4 infection, the immunological response of a Th2-skewed pancreatic milieu during recovery co-insides with, and likely favors, acinar cell proliferation.…”

Section: Cell Health and Cytoskeletonmentioning

confidence: 99%

Keratins provide virus-dependent protection or predisposition to injury in coxsackievirus-induced pancreatitis

Toivola¹,

Ostrowski²,

Baribault³

et al. 2009

CHC

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Keratins 8 and 18 (K8/K18) are the two major intermediate filament proteins in hepatocytes and pancreatic acinar cells. Acinar cell keratins are organized as cytoplasmic and apicolateral filaments. An important role of hepatocyte K8/K18 is to maintain cellular integrity, while this cytoprotective function of K8/K18 is not evident in the pancreas since keratin-deficient mice cope well with pancreatitis models. To further study the roles of keratins in the exocrine pancreas, we used coxsackievirus B4-models, CVB4-V and CVB4-P, to induce severe acute/chronic pancreatitis and acute pancreatitis, respectively, in K8-null (which lack acinar keratins) and K18-null (which lack cytoplasmic keratins) mice. Despite similar virus titers in all mice, CVB4-V resulted in 40% mortality of the K8-null mice 14 days post-infection compared to no lethality of WT and K18-null mice. In contrast, K8-null mice were far less susceptible to CVB4-P-induced damage as determined by histology and serology analysis, and they recover faster than WT and K18-null mice. After CVB4 virus infection, keratins aggregated during acinar degranulation, and K8/K18 site-specific phosphorylation was observed during degranulation and recovery. Hence, keratins significantly affect CVB4 virulence, positively or negatively, depending on the virus subtype and keratin makeup, in a virus replication-independent manner.

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Exogenous Interleukin-12 Protects against Lethal Infection with Coxsackievirus B4

Cited by 27 publications

References 34 publications

Progression or Resolution of Coxsackievirus B4-Induced Pancreatitis: a Genomic Analysis

Progression or Resolution of Coxsackievirus B4-Induced Pancreatitis: a Genomic Analysis

Intranasal Interleukin-12 Treatment for Protection against Respiratory Infection with theFrancisella tularensisLive Vaccine Strain

Keratins provide virus-dependent protection or predisposition to injury in coxsackievirus-induced pancreatitis

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