Overwintering Is Associated with Reduced Expression of Immune Genes and Higher Susceptibility to Virus Infection in Honey Bees

The eusocial honey bee, Apis mellifera, has evolved remarkable abilities to survive extreme seasonal differences in temperature and availability of resources by dividing the worker caste into two groups that differ in physiology and lifespan: summer and winter bees. Most of the recent major losses of managed honey bee colonies occur during the winter, suggesting that winter bees may have compromised immune function and higher susceptibility to diseases. We tested this hypothesis by comparing the expression of eight immune genes and naturally occurring infection levels of deformed wing virus (DWV), one of the most widespread viruses in A. mellifera populations, between summer and winter bees. Possible interactions between immune response and physiological activity were tested by measuring the expression of vitellogenin and methyl farnesoate epoxidase, a gene coding for the last enzyme involved in juvenile hormone biosynthesis. Our data show that high DWV loads in winter bees correlate with reduced expression of genes involved in the cellular immune response and physiological activity and high expression of humoral immune genes involved in antibacterial defense compared with summer bees. This expression pattern could reflect evolutionary adaptations to resist bacterial pathogens and economize energy during the winter under a pathogen landscape with reduced risk of pathogenic viral infections. The outbreak of Varroa destructor infestation could have overcome these adaptations by promoting the transmission of viruses. Our results suggest that reduced cellular immune function during the winter may have increased honey bee’s susceptibility to DWV. These results contribute to our understanding of honey bee colony losses in temperate regions.     

Immune Response to Gluten in Adult Coeliac Disease

Cultures of mesenteric node lymphocytes obtained from two adult coeliac disease patients were stimulated by gluten fraction III. No stimulation was observed in cultures of axillary node lymphocytes from one of these patients, of mesenteric node lymphocytes from the two patients with other diseases or of peripheral blood lymphocytes from adult coeliacs and normal subjects. Peripheral blood lymphocytes of two of the six adult coeliac patients responded poorly to phytohaemagglutin alone, but this was probably owing to technical factors. In a further six adult coeliacs skin tests to gluten fraction III were negative. It is suggested that delayed hypersensitivity to gluten is likely to have a secondary pathogenic role in adult coeliac disease.     

Susceptibility to Infection and Immune Response in Insular and Continental Populations of Egyptian Vulture: Implications for Conservation

Background

A generalized decline in populations of Old World avian scavengers is occurring on a global scale. The main cause of the observed crisis in continental populations of these birds should be looked for in the interaction between two factors - changes in livestock management, including the increased use of pharmaceutical products, and disease. Insular vertebrates seem to be especially susceptible to diseases induced by the arrival of exotic pathogens, a process often favored by human activities, and sedentary and highly dense insular scavengers populations may be thus especially exposed to infection by such pathogens. Here, we compare pathogen prevalence and immune response in insular and continental populations of the globally endangered Egyptian vulture under similar livestock management scenarios, but with different ecological and evolutionary perspectives.

Methods/Principal Findings

Adult, immature, and fledgling vultures from the Canary Islands and the Iberian Peninsula were sampled to determine a) the prevalence of seven pathogen taxa and b) their immunocompetence, as measured by monitoring techniques (white blood cells counts and immunoglobulins). In the Canarian population, pathogen prevalence was higher and, in addition, an association among pathogens was apparent, contrary to the situation detected in continental populations. Despite that, insular fledglings showed lower leukocyte profiles than continental birds and Canarian fledglings infected by Chlamydophila psittaci showed poorer cellular immune response.

Conclusions/Significance

A combination of environmental and ecological factors may contribute to explain the high susceptibility to infection found in insular vultures. The scenario described here may be similar in other insular systems where populations of carrion-eaters are in strong decline and are seriously threatened. Higher susceptibility to infection may be a further factor contributing decisively to the extinction of island scavengers in the present context of global change and increasing numbers of emerging infectious diseases.     

Perinatal Exposure to a Low Dose of Bisphenol A Impaired Systemic Cellular Immune Response and Predisposes Young Rats to Intestinal Parasitic Infection

Perinatal exposure to the food contaminant bisphenol A (BPA) in rats induces long lasting adverse effects on intestinal immune homeostasis. This study was aimed at examining the immune response to dietary antigens and the clearance of parasites in young rats at the end of perinatal exposure to a low dose of BPA. Female rats were fed with BPA [5 µg/kg of body weight/day] or vehicle from gestational day 15 to pup weaning. Juvenile female offspring (day (D)25) were used to analyze immune cell populations, humoral and cellular responses after oral tolerance or immunization protocol to ovalbumin (OVA), and susceptibility to infection by the intestinal nematode Nippostrongylus brasiliensis (N. brasiliensis). Anti-OVA IgG titers following either oral tolerance or immunization were not affected after BPA perinatal exposure, while a sharp decrease in OVA-induced IFNγ secretion occurred in spleen and mesenteric lymph nodes (MLN) of OVA-immunized rats. These results are consistent with a decreased number of helper T cells, regulatory T cells and dendritic cells in spleen and MLN of BPA-exposed rats. The lack of cellular response to antigens questioned the ability of BPA-exposed rats to clear intestinal infections. A 1.5-fold increase in N. brasiliensis living larvae was observed in the intestine of BPA-exposed rats compared to controls due to an inappropriate Th1/Th2 cytokine production in infected jejunal tissues. These results show that perinatal BPA exposure impairs cellular response to food antigens, and increases susceptibility to intestinal parasitic infection in the juveniles. This emphasized the maturing immune system during perinatal period highly sensitive to low dose exposure to BPA, altering innate and adaptative immune response capacities in early life.     

糖尿病小鼠对H5N1病毒的易感性及灭活疫苗诱导的免疫反应

糖尿病患者免疫功能低下,是流感病毒感染的高危人群.研制有效的流感病毒疫苗对糖尿病患者尤为重要.以注射STZ的方法建立糖尿病小鼠模型,比较糖尿病小鼠和健康小鼠对H5N1病毒易感性的差异.病毒感染3 d后糖尿病小鼠的肺部病毒滴度比健康小鼠高,显示糖尿病小鼠对H5N1病毒更易感.用一次免疫的方法接种不同剂量的H5N1灭活疫苗(单独免疫或与佐剂共同免疫),比较其在糖尿病小鼠和健康小鼠诱导抗体应答的能力.一次免疫H5N1流感病毒灭活疫苗可诱导糖尿病小鼠产生体液免疫应答,但其抗体量低于健康小鼠,增加疫苗剂量可提高抗体水平.佐剂能增强H5N1全病毒灭活疫苗在糖尿病小鼠体内诱导的抗体反应.     

Simulation and Prediction of the Adaptive Immune Response to Influenza A Virus Infection

The cellular immune response to primary influenza virus infection is complex, involving multiple cell types and anatomical compartments, and is difficult to measure directly. Here we develop a two-compartment model that quantifies the interplay between viral replication and adaptive immunity. The fidelity of the model is demonstrated by accurately confirming the role of CD4 help for antibody persistence and the consequences of immune depletion experiments. The model predicts that drugs to limit viral infection and/or production must be administered within 2 days of infection, with a benefit of combination therapy when administered early, and cytotoxic CD8 T cells in the lung are as effective for viral clearance as neutralizing antibodies when present at the time of challenge. The model can be used to investigate explicit biological scenarios and generate experimentally testable hypotheses. For example, when the adaptive response depends on cellular immune cell priming, regulation of antigen presentation has greater influence on the kinetics of viral clearance than the efficiency of virus neutralization or cellular cytotoxicity. These findings suggest that the modulation of antigen presentation or the number of lung resident cytotoxic cells and the combination drug intervention are strategies to combat highly virulent influenza viruses. We further compared alternative model structures, for example, B-cell activation directly by the virus versus that through professional antigen-presenting cells or dendritic cell licensing of CD8 T cells.Understanding how the immune system combats influenza virus infection and how the virus can affect the immune system is crucial to predicting and designing prophylactic and therapeutic strategies against the infection (58). Antigenic shift and antigenic drift alter the degree to which preexisting immunity can control the virus. These factors also influence whether different arms of the adaptive immune system can cross-react against new strains of the virus. For example, shifts of the hemagglutinin (HA) and neuraminidase (NA) protein sequences limit the ability of antibodies to neutralize new variants of the virus and may make cross-reactive T-cell responses to conserved viral proteins more important. Other viral proteins, such as NS1, affect both the induction of type I interferon as well as the susceptibility of infected cells to interferon-mediated inhibition of viral gene expression (43). The efficiencies of viral replication and cell-to-cell viral spread are altered by mutations in the viral matrix and polymerase genes, while the survival of infected cells can be altered by the viral PB1-F2 protein. These attributes are influenced by mutations in the viral matrix (50, 51) and polymerase (30, 69) genes, while the survival of infected cells can be altered by the viral PB1-F2 protein (17). The multigenic aspect of influenza virus pathogenesis makes experimental prediction difficult and time-consuming. Computer simulation tools would be useful to independently dissect the potential contribution and relative importance of each factor or to investigate unexpected scenarios that are difficult to replicate experimentally.Mathematical models and computer simulations have been widely used to study viral dynamics and immune responses to viral infections, such as human immunodeficiency virus type 1 (HIV-1) and simian immunodeficiency viruses (SIV), lymphocytic choriomeningitis virus (19, 55, 60, 61), and influenza A virus (3, 7, 8, 13, 34, 35, 52). More complex compartmental models of the immune system (4, 23) and models incorporating differential delay equations (21, 48, 68) have been used to better reflect the time that cells reside in a particular compartment or the duration of transit between compartments. In this study, we sought to develop a two-compartment mathematical model to assess the individual contributions of antigen presentation and activation of naïve T and B cells by antigen-presenting cells (APC), CD4 T-cell help, CD8 T-cell-mediated cytotoxicity, B cells, and antibody to control influenza A virus (IAV) infection and to explore the influence of anatomical location. We developed a model which represented published experimental findings on primary influenza virus infection. More importantly, the model was used to explore alternative structures for interactions between virus and immune cells, for example, comparing virus kinetics when antigen delivery and immune cell priming occurred through direct interaction of virus and immune cells or through a cellular intermediate. The model predicts that, under some circumstances, changes affecting antigen presentation more strongly impacted viral kinetics than other viral or immune factors (28, 73, 75, 78). This model highlights the importance of the assumptions used to synthesize a model and gaps in our understanding of the immune response regulating primary influenza virus infection. We discuss the implications of these findings for future influenza virus research and theories of influenza virus virulence based on influenza virus-immune system interactions.     

Chronic Schistosoma japonicum Infection Reduces Immune Response to Vaccine against Hepatitis B in Mice

Background

Hepatitis B and schistosomiasis are most prevalent in Africa and Asia, and co-infections of both are frequent in these areas. The immunomodulation reported to be induced by schistosome infections might restrict immune control of hepatitis B virus (HBV) leading to more severe viral infection. Vaccination is the most effective measure to control and prevent HBV infection, but there is evidence for a reduced immune response to the vaccine in patients with chronic schistosomiasis japonica.

Methodology/Principal Findings

In this paper, we demonstrate in a mouse model that a chronic Schistosoma japonicum infection can inhibit the immune response to hepatitis B vaccine (HBV vaccine) and lead to lower production of anti-HBs antibodies, interferon-γ (IFN-γ) and interleukin-2 (IL-2). After deworming with Praziquantel (PZQ), the level of anti-HBs antibodies gradually increased and the Th2-biased profile slowly tapered. At 16 weeks after deworming, the levels of anti-HBs antibodies and Th1/Th2 cytokines returned to the normal levels.

Conclusions/Significance

The results suggest that the preexisting Th2-dominated immune profile in the host infected with the parasite may down–regulate levels of anti-HBs antibodies and Th1 cytokines. To improve the efficacy of HBV vaccination in schistosome infected humans it may be valuable to treat them with praziquantel (PZQ) some time prior to HBV vaccination.     

Lack of IL-6 during Coxsackievirus Infection Heightens the Early Immune Response Resulting in Increased Severity of Chronic Autoimmune Myocarditis

Background

Chronic myocarditis is often initiated by viral infection, the most common of which is coxsackievirus infection. The precise mechanism by which viral infection leads to chronic autoimmune pathology is poorly understood, however it is clear that the early immune response plays a critical role. Previous results have shown that the inflammatory cytokine interleukin (IL)-6 is integral to the development of experimental-induced autoimmune myocarditis. However, the function of IL-6 during viral-mediated autoimmunity has yet to be elucidated.

Methods and Results

To address the requirement of IL-6 during disease induction, IL-6 deficient mice were infected with coxsackievirus B3 (CB3). Following infection, mice lacking IL-6 developed increased chronic autoimmune disease pathology compared to wild type controls without a corresponding change in the level of viral replication in the heart. This increase in disease severity was accompanied by elevated levels of TNF-α, MCP-1, IL-10, activated T cells and cardiac infiltrating macrophage/monocytes. Injection of recombinant IL-6 early following infection in the IL-6 deficient mice was sufficient to lower the serum cytokines TNF-α and IL-10 as well as the serum chemokines MCP-1, MIP-1β, RANTES and MIG with a corresponding decrease in the chronic disease pathology strongly suggests an important regulatory role for IL-6 during the early response.

Conclusions

While IL-6 plays a pathogenic role in experimental-induced autoimmune disease, its function following viral-induced autoimmunity is not reprised. By regulating the early immune response and thereby controlling the severity of chronic disease, IL-6 directs the outcome of chronic autoimmune myocarditis.     

Body Temperature Changes in Young and Adult Rats in Response to Emotionally Significant Sound and Immobilization

Experiments with rats have shown that thermoregulation under normal conditions and in response to stressful factors (immobilization, emotionally significant sound) is different in animals of different age. The effect of these stressful factors leads to more significant temperature changes in the group of young animals, as compared with the adult ones.     

Innate Immune Response to Arenaviral Infection: A Focus on the Highly Pathogenic New World Hemorrhagic Arenaviruses

Arenaviruses are enveloped, negative-stranded RNA viruses that belong to the family Arenaviridae. This diverse family can be further classified into OW (Old World) and NW (New World) arenaviruses based on their antigenicity, phylogeny, and geographical distribution. Many of the NW arenaviruses are highly pathogenic viruses that cause systemic human infections characterized by hemorrhagic fever and/or neurological manifestations, constituting public health problems in their endemic regions. NW arenavirus infection induces a variety of host innate immune responses, which could contribute to the viral pathogenesis and/or influence the final outcome of virus infection in vitro and in vivo. On the other hand, NW arenaviruses have also developed several strategies to counteract the host innate immune response. We will review current knowledge regarding the interplay between the host innate immune response and NW arenavirus infection in vitro and in vivo, with emphasis on viral-encoded proteins and their effect on the type I interferon response.     

A Regulatory Polymorphism in HAVCR2 Modulates Susceptibility to HIV-1 Infection

The HAVCR2 gene encodes TIM-3, an immunoglobulin superfamily member expressed by exhausted CD8+ T cells during chronic viral infection. We investigated whether genetic variation at HAVCR2 modulates the susceptibility to HIV-1 acquisition; specifically we focused on a 3′ UTR variant (rs4704846, A/G) that represents a natural selection target. We genotyped rs4704846 in three independent cohorts of HIV-1 exposed seronegative (HESN) individuals with different geographic origin (Italy and Spain) and distinct route of exposure to HIV-1 (sexual and injection drug use). Matched HIV-1 positive subjects and healthy controls were also analyzed. In all case-control cohorts the minor G allele at rs4704846 was more common in HIV-1 infected individuals than in HESN, with healthy controls showing intermediate frequency. Results from the three association analyses were combined through a random effect meta-analysis, which revealed no heterogeneity among samples (Cochrane''s Q, p value =  0.89, I² =  0) and yielded a p value of 6.8 ×10⁻⁴. The minor G allele at rs4704846 was found to increase HAVCR2 expression after in vitro HIV-1 infection. Thus, a positively selected polymorphism in the 3′ UTR, which modulates HAVCR2 expression, is associated with the susceptibility to HIV-1 infection. These data warrant further investigation into the role of TIM-3 in the prevention and treatment of HIV-1/AIDS.     

Immune Response to and Histopathology of Campylobacter jejuni Infection in Ferrets (Mustela putorius furo)

Campylobacter jejuni is 1 of the most common enteric bacterial pathogens worldwide. The mechanisms of pathogenesis remain obscure, in part because of limitations of small animal models. Young ferrets develop diarrhea when fed C. jejuni, but their pathology and the immune response after infection have not been examined in detail. In the present study, we examined the pathogenesis of C. jejuni CG8421 and associated immune responses in ferrets. After oral infection with C. jejuni CG8421, 86.7% of the animals developed diarrhea and inflammatory responses that were similar to those seen in human infection. Pronounced histopathologic changes in the colonic mucosa of infected animals were observed during the acute phase (days 1 through 3) of infection. Electron micrographs of colonic epithelium revealed disruption of the villi and internalized bacteria that were not within membrane vacuoles. During the acute phase, C. jejuni was isolated from the livers of 7 of 9 (78%) animals, and bacteria were visualized immunohistochemically in the livers from 5 of the 7 animals (71%) from which C. jejuni was isolated. A vigorous systemic and mucosal immune response to Campylobacter antigens was elicited after infection of ferrets. The data presented contribute to the current knowledge of the pathogenicity of and immunologic response to C. jejuni CG8421 in ferrets and better understanding of this model.Abbreviation: ASC, antibody-secreting cellsCampylobacter jejuni are gram-negative, spiral, microaerophilic, motile bacteria and 1 of the most common enteric bacterial pathogens globally.^15,20 The annual incidence of C. jejuni diarrheal disease varies geographically, ranging from sporadic infections in young adults in developed countries²⁸ to as frequent as 40,000 per 100,000 among children living in hyperendemic regions.¹⁵ In addition, C. jejuni is the primary cause of ‘traveler''s diarrhea’ in various regions of the world.^39,41,44 The clinical disease of C. jejuni infection has a wide spectrum of symptoms, varying from a mild, transient watery diarrhea to a bloody diarrhea with severe abdominal cramps and fever. C. jejuni infection also is associated with development of Guillain–Barré syndrome.⁵¹ Most strains of C. jejuni contain lipooligosaccharides that mimic human gangliosides structurally. Antibodies against these lipooligosaccharide structures lead to an autoimmune response, resulting in Guillain–Barré syndrome.⁵²Despite extensive study, little is understood about the mechanism by which C. jejuni causes diarrheal disease. Various Campylobacter small animal models have been reported, but these require surgical manipulation,^13,46 administration of chemicals or antibiotics (or both),^17,26,30 or inoculation by an unnatural route.⁵ None of these published models incorporate the natural route of infection. Although several immunodeficient mouse models have been reported,^35,36,49 the applicability of these models for studying the pathogenesis and immune response of natural infection is limited. An adult mouse lung model has been described that may be useful for studying pathogenesis and inflammatory response and acquired immunity, but the route of infection is not the same as that in humans.^1,5 Unlike other small animals, naïve ferrets (younger than 11 wk) intragastrically inoculated with C. jejuni developed mild to moderate diarrhea with mucus, fecal leukocytes or frank blood that lasted for as long as 3 d and remained colonized for as long as 8 d.^9,10,18 Moreover, on rechallenge with the homologous bacterial strain, ferrets asymptomatically excreted C. jejuni in their stools.¹⁰ The observation of resistance to disease, but not to infection, is similar to findings from human studies, in which protection against disease developed before colonization resistance.¹¹ Ferrets have been used to evaluate vaccines against C. jejuni¹⁴ and in molecular pathogenesis studies using strain 81-176 to confirm a role in virulence for capsular polysaccharide and flagellar glycans.^3,21 However, we evaluated the histopathology and immune response after C. jejuni infection in ferrets in more detail in the present study.C. jejuni CG8421 was isolated from a case of dysentery in Thailand. It has an lipooligosaccharide core that, as shown by chemical analyses, lacks all ganglioside mimicry.³⁸ The absence of ganglioside mimicry is predicted to reduce the risk of Guillain–Barré syndrome. We selected strain CG8421 for the current studies as part of an evaluation of a potential strain for use in future human vaccine challenge studies. Here we report the pathogenesis, histopathology, inflammatory, and immune responses after oral infection of ferrets with C. jejuni strain CG8421.     

Isolation of an Antigen of Neisseria gonorrhoeae Involved in the Human Immune Response to Gonococcal Infection

Ion-exchange chromatography was used to isolate a fraction from disrupted gonococci which reacts with sera from patients with gonococcal disease in complement-fixation and gel-diffusion tests. This antigenic fraction was shown to be the same as that previously described as having been isolated by gel filtration. The method reported here has the advantage of greater rapidity of isolation together with some improvement in purity.     

Neutrophil Extracellular Traps are Involved in the Innate Immune Response to Infection with Leptospira

NETosis is a process by which neutrophils extrude their DNA together with bactericidal proteins that trap and/or kill pathogens. In the present study, we evaluated the ability of Leptospira spp. to induce NETosis using human ex vivo and murine in vivo models. Microscopy and fluorometric studies showed that incubation of human neutrophils with Leptospira interrogans serovar Copenhageni strain Fiocruz L1-130 (LIC) resulted in the release of DNA extracellular traps (NETs). The bacteria number, pathogenicity and viability were relevant factors for induction of NETs, but bacteria motility was not. Entrapment of LIC in the NETs resulted in LIC death; however, pathogenic but not saprophytic Leptospira sp. exerted nuclease activity and degraded DNA. Mice infected with LIC showed circulating NETs after 2 days post-infection (dpi). Depletion of neutrophils with mAb1A8 significantly reduced the amount of intravascular NETs in LIC-infected mice, increasing bacteremia at 3 dpi. Although there was a low bacterial burden, scarce neutrophils and an absence of inflammation in the early stages of infection in the kidney and liver, at the beginning of the leptospiruric phase, the bacterial burden was significantly higher in kidneys of neutrophil-depleted-mice compared to non-depleted and infected mice. Surprisingly, interstitial nephritis was of similar intensity in both groups of infected mice. Taken together, these data suggest that LIC triggers NETs, and that the intravascular formation of these DNA traps appears to be critical not only to prevent early leptospiral dissemination but also to preclude further bacterial burden.     

The Role of Galectin-1 and Galectin-3 in the Mucosal Immune Response to Citrobacter rodentium Infection

Despite their abundance at gastrointestinal sites, little is known about the role of galectins in gut immune responses. We have therefore investigated the Citrobacter rodentium model of colonic infection and inflammation in Galectin-1 or Galectin-3 null mice. Gal-3 null mice showed a slight delay in colonisation after inoculation with C. rodentium and a slight delay in resolution of infection, associated with delayed T cell, macrophage and dendritic cell infiltration into the gut mucosa. However, Gal-1 null mice also demonstrated reduced T cell and macrophage responses to infection. Despite the reduced T cell and macrophage response in Gal-1 null mice, there was no effect on C. rodentium infection kinetics and pathology. Overall, Gal-1 and Gal-3 play only a minor role in immunity to a gut bacterial pathogen.