Antiviral antibodies attenuate T-cell-mediated immunopathology following acute lymphocytic choriomeningitis virus infection.

The role of antiviral antibody in resistance to acute lymphocytic choriomeningitis virus infection has been examined by passive transfer of monoclonal antibodies and intracerebral challenge infection. Protection of mice from lethal T-cell-mediated acute disease was observed following passive administration of antibodies either 1 day before or up to 2 days after infection. Viral replication was suppressed in protected mice, and the cytotoxic T-cell response to virus was also diminished. Virus was cleared from the brain and other tissues of protected mice without development of lethal immunopathology, suggesting that preexisting antibody may play a significant role in modulating potentially destructive effects of T-cell-mediated immune responses to pathogens.     

Rabbitpox virus and vaccinia virus infection of rabbits as a model for human smallpox

The threat of smallpox release and use as a bioweapon has encouraged the search for new vaccines and antiviral drugs, as well as development of new small-animal models in which their efficacy can be determined. Here, we reinvestigate a rabbit model in which the intradermal infection of rabbits with very low doses of either rabbitpox virus (RPV) or vaccinia virus Western Reserve (VV-WR) recapitulates many of the clinical features of human smallpox. Following intradermal inoculation with RPV, rabbits develop systemic disease characterized by extensive viremia, numerous secondary lesions on the skin and mucocutaneous tissues, severe respiratory disease, death by 9 days postinfection, and, importantly, natural aerosol transmission between animals. Contrary to previous reports, intradermal infection with VV-WR also resulted in a very similar lethal systemic disease in rabbits, again with natural aerosol transmission between animals. When sentinel and index animals were cohoused, transmission rates approached 100% with either virus, with sentinel animals exhibiting a similar, severe disease. Lower rates of transmission were observed when index and sentinel animals were housed in separate cages. Sentinel animals infected with RPV with one exception succumbed to the disease. However, the majority of VV-WR-infected sentinel animals, while becoming seriously ill, survived. Finally, we tested the efficacy of the drug 1-O-hexadecyloxypropyl-cidofovir in the RPV/rabbit model and found that an oral dose of 5 mg/kg twice a day for 5 days beginning 1 day before infection was able to completely protect rabbits from lethal disease.     

Protective immunity against hepatitis C virus infection

There is increasing evidence that a small percentage of individuals exposed to the hepatitis C virus have the capacity to generate a strong cellular immune response against the virus and avoid persistent infection, and perhaps do so repeatedly after re-exposure. This article reviews the evidence that the responses identified in this unique group of individuals represent the protective immunity that will need to be elicited by hepatitis C virus vaccines.     

Associations of HLA-DP variants with hepatitis B virus infection in southern and northern Han Chinese populations: a multicenter case-control study

Background

Human leukocyte antigen DP (HLA-DP) locus has been reported to be associated with hepatitis B virus (HBV) infection in populations of Japan and Thailand. We aimed to examine whether the association can be replicated in Han Chinese populations.

Methodology/Principal Findings

Two HLA-DP variants rs2395309 and rs9277535 (the most strongly associated SNPs from each HLA-DP locus) were genotyped in three independent Han cohorts consisting of 2 805 cases and 1 796 controls. By using logistic regression analysis, these two SNPs in the HLA-DPA1 and HLA-DPB1 genes were significantly associated with HBV infection in Han Chinese populations (P = 0.021∼3.36×10⁻⁸ at rs2395309; P = 8.37×10⁻³∼2.68×10⁻¹⁰ at rs9277535). In addition, the genotype distributions of both sites (rs2395309 and rs9277535) were clearly different between southern and northern Chinese population (P = 8.95×10⁻⁵ at rs2395309; P = 1.64×10⁻⁹ at rs9277535). By using asymptomatic HBV carrier as control group, our study showed that there were no associations of two HLA-DP variants with HBV progression (P = 0.305∼0.822 and 0.163∼0.881 in southern Chinese population, respectively; P = 0.097∼0.697 and 0.198∼0.615 in northern Chinese population, respectively).

Conclusions

Our results confirmed that two SNPs (rs2395309 and rs9277535) in the HLA-DP loci were strongly associated with HBV infection in southern and northern Han Chinese populations, but not with HBV progression.     

KIR and HLA loci are associated with hepatocellular carcinoma development in patients with hepatitis B virus infection: a case-control study

Background

Natural killer (NK) cells activation has been reported to contribute to inflammation and liver injury during hepatitis B virus (HBV) infection both in transgenic mice and in patients. However, the role of NK cells in the process of HBV-associated hepatocellular carcinoma (HCC) development has not been addressed. Killer cell immunoglobulin-like receptors (KIRs) are involved in regulating NK cell activation through recognition of specific human leukocyte antigen (HLA) class I allotypes.

Methodology/Principal Findings

To investigate whether KIR and HLA genes could influence the risk of HBV-associated HCC development, 144 HBV-infected patients with HCC and 189 well-matched HBV infectors with chronic hepatitis or cirrhosis as non-HCC controls were enrolled in this study. The presence of 12 loci of KIR was detected individually. HLA-A, -B, -C loci were genotyped with high-resolution. HLA-C group 1 homozygote (OR = 2.02; p = 0.005), HLA-Bw4-80I (OR = 2.67; p = 2.0E-04) and combination of full-length form and 22 bp-deleted form of KIR2DS4 (KIR2DS4/1D) (OR = 1.89; p = 0.017) were found associated with HCC incidence. When the combined effects of these three genetic factors were evaluated, more risk factors were observed correlating with higher odds ratios for HCC incidence (P trend = 7.4E-05). Because all the risk factors we found have been reported to result in high NK cell functional potential by previous studies, our observations suggest that NK cell activation may contribute to HBV-associated HCC development.

Conclusions/Significance

In conclusion, this study has identified significant associations that suggest an important role for NK cells in HCC incidence in HBV-infected patients. Our study is useful for HCC surveillance and has implications for novel personalized therapy strategy development aiming at HCC prevention in HBV-infected patients.     

抗病毒感染固有免疫应答的信号转导

入侵病毒的探知和适应性免疫应答启动均依靠固有免疫系统。三种模式识别受体(PRRs)在宿主防御系统第一线占据极其重要地位:Toll样受体、维甲酸诱导基因I样受体、核苷酸结合寡聚化结构域样受体。PRRs识别病原相关分子模式(PAMP)或危险信号分子模式(DAMPs)启动和调节固有免疫和适应性免疫应答。每种PRR都有单独的识别配体和细胞定位。激活的PRRs将信号分子传递给其配体分子(MyD88,TRIF,IRAK,IPS-1),配体活化后作为信使激活信号途径下游激酶(IKK复合物,MAPKs,TBK1,RIP-1)和转录因子(NF-κB,AP-1,IRF3),最终产生细胞因子、趋化因子、促炎细胞因子和I型干扰素。本文重点讨论PRRs信号通路及该领域取得的成果,以期为人类健康和免疫疾病防治提供策略。     

Lack of association between vascular dementia and Chlamydia pneumoniae infection: a case-control study

Background

Chronic inflammation appears to play a role in the pathogenesis of vascular dementia. Given the association between Chlamydia pneumoniae and stroke, the possibility exists that previous exposure to C. pneumoniae may play a role in vascular dementia. The objective of this study was to determine if there was an association between serological evidence of C. pneumoniae infection or inflammatory markers with vascular dementia.

Methods

28 case-patients with vascular dementia at a geriatric clinic and 24 caregiver-controls were tested for C. pneumoniae IgG and IgA antibodies. The association between vascular dementia and C. pneumoniae titres as well as inflammatory markers was estimated by using both conditional logistic regression and stratified logistic regression.

Results

When matched cases were compared to controls, there was no significant difference in elevated C. pneumoniae specific IgG antibodies (titre ≥ 1:32), odds ratio [OR] 1.3 (95% confidence intervals [CI] 0.3 to 6.0), p = 0.71, or in elevated C. pneumoniae specific IgA antibodies (titre ≥ 1:16), OR 2.0 (95%CI 0.5 to 8.0), p = 0.33 indicative of past or persistent C. pneumoniae infection. Similarly, no difference in high IgG or IgA antibody levels (IgG titre ≥ 1:512 or IgA titre ≥ 1:64) between the two groups, indicative of recent C. pneumoniae infection, was found, OR 0.4 (95%CI 0.1 to 2.1), p = 0.27. For C-reactive protein (CRP), the mean difference between 18 matched pairs (case – control) was – 3.33 mg/L. There was no significant difference between cases and controls when comparing log transformed values, OR 0.03 (95%CI 0.00 to 2.89), p = 0.13 or comparing CRP values above or below the median, OR 0.8 (95%CI 0.2 to 3.4), p = 0.71. For fibrinogen, the mean difference between pairs (case – control) was -0.07 g/L. There was no statistical difference between cases and controls when comparing log transformed values, OR 0.6 (95%CI 0.0 to 31.2), p = 0.79 or between fibrinogen values above and below the median, OR = 0.5 (95%CI 0.1 to 2.0), p = 0.50.

Conclusion

We found no evidence for a significant association between C. pneumoniae infection, inflammatory markers such as CRP and fibrinogen, and vascular dementia.

     

Cellular and humoral immunity following Snow Mountain virus challenge

Little is known about the immune response to noroviruses. To elucidate the immunobiology of norovirus infection in humans, 15 volunteers were challenged with Snow Mountain virus (SMV), a genogroup 2 norovirus. We assessed the cellular and humoral immune response and infection by analyzing stool, serum, saliva, and peripheral blood mononuclear cell (PBMC) responses pre- and postchallenge. In contrast to Norwalk virus (NV), SMV infection was not dependent upon blood group secretor status. Nine of 15 volunteers were infected and showed a >/=4-fold increase over the prechallenge anti-SMV serum immunoglobulin G (IgG) titer, mostly subclass IgG1. Although serum IgG elicited by SMV infection was cross-reactive with Hawaii virus (HV), another genogroup 2 norovirus, salivary IgA was less cross-reactive. Neither SMV-elicited serum IgG nor salivary IgA cross-reacted with NV, a genogroup 1 norovirus. Significant increases in serum gamma interferon (IFN-gamma) and IL-2, but not IL-6 or IL-10, were noted on day 2 postchallenge. For the majority of volunteers, both infected and uninfected, PBMCs stimulated with norovirus virus-like particles secreted IFN-gamma and other Th1 cytokines, suggesting previous norovirus exposure in most volunteers. Like the IgG antibodies, the SMV-activated T cells were cross-reactive with HV but not NV. IFN-gamma production was dependent upon CD4(+) cells, consistent with a predominant, but not exclusive, Th1 response. To our knowledge, this is the first report characterizing T-cell and cytokine responses following live norovirus challenge.     

Bilateral optic neuritis in a child following Epstein-Barr virus infection

A rare case of bilateral optic neuritis is presented in a child with no light perception. Ophthalmic examination revealed dilated pupils without reaction to the light, swollen optic discs with small peripapillary hemorrhages in both eyes. Serology revealed evidence of recent Epstein-Barr virus infection. After treatment with high dose of corticosteroid visual acuity gradually improved. After four months visual acuity was normal despite complete pallor of the optic disc. Ebstein-Barr virus infection should be considered in the differential diagnosis of bilateral optic neuritis in a child with severe bilateral visual loss.