Protective immune responses against West Nile virus are primed by distinct complement activation pathways

Mehlhop, Erin; Diamond, Michael S.

doi:10.1084/jem.20052388

Cited by 160 publications

(172 citation statements)

References 69 publications

(116 reference statements)

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“…1B). Caspase 3/7 activity was enhanced beginning on day 6 and remained elevated on days 8 and 10 after infection, correlating with viral entry into the CNS and the onset of encephalitic symptoms and death (9,33,48).…”

Section: Caspase 3 Is Activated In the Cns After Wnv Infectionmentioning

confidence: 98%

Caspase 3-Dependent Cell Death of Neurons Contributes to the Pathogenesis of West Nile Virus Encephalitis

Samuel¹,

Morrey

Diamond

2007

J Virol

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162

176

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West Nile virus (WNV) is a neurotropic, arthropod-borne flavivirus that has become a significant global cause of viral encephalitis. To examine the mechanisms of WNV-induced neuronal death and the importance of apoptosis in pathogenesis, we evaluated the role of a key apoptotic regulator, caspase 3. WNV infection induced caspase 3 activation and apoptosis in the brains of wild-type mice. Notably, congenic caspase 3 ؊/؊ mice were more resistant to lethal WNV infection, although there were no significant differences in the tissue viral burdens or the kinetics of viral spread. Instead, decreased neuronal death was observed in the cerebral cortices, brain stems, and cerebella of caspase 3 ؊/؊ mice. Analogously, primary central nervous system (CNS)-derived neurons demonstrated caspase 3 activation and apoptosis after WNV infection, and treatment with caspase inhibitors or a genetic deficiency in caspase 3 significantly decreased virus-induced death. These studies establish that caspase 3-dependent apoptosis contributes to the pathogenesis of lethal WNV encephalitis and suggest possible novel therapeutic targets to restrict CNS injury.

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Section: Caspase 3 Is Activated In the Cns After Wnv Infectionmentioning

confidence: 98%

Caspase 3-Dependent Cell Death of Neurons Contributes to the Pathogenesis of West Nile Virus Encephalitis

Samuel¹,

Morrey

Diamond

2007

J Virol

Self Cite

162

176

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“…The most direct support for this is the reduced HA titers against high doses of SRBCs administered to C1qA −/− mice (29). Responses to malaria parasites or West Nile virus in C1q-deficient mice were much less affected than responses to SRBCs, and were even higher than in WT mice in some cases (24,30).…”

Section: Igm Mutation | Natural Igmmentioning

confidence: 99%

“…Mice lacking a functional alternative pathway because of deletion of factor B have normal Ab responses to SRBCs (23) as well as to West Nile virus (24), indicating that the alternative pathway is not required. Mannan-binding lectin (MBL) KO mice show a complex phenotype, with normal, moderately higher, or moderately lower Ab responses than WT controls (25)(26)(27)(28).…”

Section: Igm Mutation | Natural Igmmentioning

confidence: 99%

Requirement for complement in antibody responses is not explained by the classic pathway activator IgM

Rutemark

Alicot

Bergman

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Animals lacking complement factors C1q, C2, C3, or C4 have severely impaired Ab responses, suggesting a major role for the classic pathway. The classic pathway is primarily initiated by antigen–Ab complexes. Therefore, its role for primary Ab responses seems paradoxical because only low amounts of specific Abs are present in naive animals. A possible explanation could be that the classic pathway is initiated by IgM from naive mice, binding with sufficient avidity to the antigen. To test this hypothesis, a knock-in mouse strain, Cμ13, with a point mutation in the gene encoding the third constant domain of the μ-heavy chain was constructed. These mice produce IgM in which proline in position 436 is substituted with serine, a mutation previously shown to abrogate the ability of mouse IgM to activate complement. Unexpectedly, the Ab response to sheep erythrocytes and keyhole limpet hemocyanin in Cμ13 mice was similar to that in WT mice. Thus, although secreted IgM and the classic pathway activation are both required for the normal primary Ab response, this does not require that IgM activate C. This led us to test Ab responses in animals lacking one of three other endogenous activators of the classic pathway: specific intracellular adhesion molecule-grabbing nonintegrin R1, serum amyloid P component, and C-reactive protein. Ab responses were also normal in these animals.

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“…Therefore mosquito saliva, by inhibiting factor Xa, decreases the production of C5a, thereby suppressing these downstream effects that hasten the destruction of pathogens. Interestingly, a recent study confirmed that complement plays a critical role in controlling West Nile virus (WNV) infection, a mosquitotransmitted flavivirus (Mehlhop and Diamond 2006).…”

Section: The Enigma Of Immunomodulation In Rapid Feeding Vectorsmentioning

confidence: 99%

The enhancement of arbovirus transmission and disease by mosquito saliva is associated with modulation of the host immune response

Schneider

Higgs

2008

Transactions of the Royal Society of Tropical Medicine and Hygi

227

198

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SUMMARYArthropod-borne viruses have emerged as a major human health concern. Viruses transmitted by mosquitoes are the cause of the most serious and widespread arbovirus diseases worldwide and are ubiquitous in both feral and urban settings. Arboviruses, including dengue and West Nile virus are injected into vertebrates within mosquito saliva during mosquito feeding. Mosquito saliva contains anti-haemostatic, anti-inflammatory and immunomodulatory molecules that facilitate the acquisition of a blood-meal. Collectively, studies investigating the effects of mosquito saliva on the vertebrate immune response suggest that at high concentrations salivary proteins are immmunosuppressive, whereas lower concentrations modulate the immune response; specifically, T H 1 and antiviral cytokines are down-regulated, while T H 2 cytokines are unaffected or amplified. As a consequence, mosquito saliva can impair the anti-viral immune response thus affecting viral infectiousness and host survival. Mounting evidence suggests that this is a mechanism whereby arbovirus pathogenicity is enhanced. In a range of disease models, including various hosts, mosquito species, and arthropodborne viruses, mosquito saliva and/or feeding is associated with a potentiation of virus infection. Compared to arbovirus infection initiated in absence of the mosquito or its saliva, infection including mosquito saliva leads to an increase in virus transmission, host susceptibility, viraemia, disease progression, and mortality.Keywords arthropod-borne virus; mosquito saliva; immunomodulation; disease enhancement Most arthropod-borne (arbo)viruses of public health significance are mosquito-borne, and thus transmitted to vertebrates via the feeding of an infected mosquito. For a mosquito to

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Protective immune responses against West Nile virus are primed by distinct complement activation pathways

Cited by 160 publications

References 69 publications

Caspase 3-Dependent Cell Death of Neurons Contributes to the Pathogenesis of West Nile Virus Encephalitis

Caspase 3-Dependent Cell Death of Neurons Contributes to the Pathogenesis of West Nile Virus Encephalitis

Requirement for complement in antibody responses is not explained by the classic pathway activator IgM

The enhancement of arbovirus transmission and disease by mosquito saliva is associated with modulation of the host immune response

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