High Pathogen Burden Research Articles

Infectious diseases, IL6 −174G > C polymorphism, and human development

Interleukin-6 (IL6) is a pro-inflammatory cytokine that is required for resistance against many pathogens. However, sustained IL6 activity can cause tissue damage in the periphery and brain. Previous studies have shown that populations in disease-endemic regions adapt by selecting the high-producing G-allele at the −174G>C (rs1800795) polymorphism, while others have linked increased IL6 to cognitive impairments. The present study sought to determine whether up-regulation of IL6 by the G-allele at rs1800795 polymorphism in disease-endemic regions was associated with increased cognitive deficits and corollary reductions in social, economic, and political development.We tested these hypotheses in a global sample of 189 nations with World Health Organization ratings for infectious diseases. We also included the Historical Pathogen Prevalence index, a measure of national average intelligence (IQ), and the United Nation Human Development Index (HDI) including per capita income, life expectancy, child mortality, and fertility rate. IL6 −174G>C allele frequencies were obtained from 171,168 individuals spanning 84 nations.The high-producing G-allele frequency was positively correlated with infectious disease ranking (r=0.745, P<0.001) and negatively with IQ (r=−0.524, P<0.001) and HDI (r=−0.671, P<0.001). These robust findings suggest that in regions with a high pathogen burden the need for a strong IL6 response is accompanied by cognitive deficits and reduced HDI ranking.

Infectious disease, behavioural flexibility and the evolution of culture in primates.

Culturally transmitted traits are observed in a wide array of animal species, yet we understand little about the costs of the behavioural patterns that underlie culture, such as innovation and social learning. We propose that infectious diseases are a significant cost associated with cultural transmission. We investigated two hypotheses that may explain such a connection: that social learning and exploratory behaviours (specifically, innovation and extractive foraging) either compensate for existing infection or increase exposure to infectious agents. We used Bayesian comparative methods, controlling for sampling effort, body mass, group size, geographical range size, terrestriality, latitude and phylogenetic uncertainty. Across 127 primate species, we found a positive association between pathogen richness and rates of innovation, extractive foraging and social learning. This relationship was driven by two independent phenomena: socially contagious diseases were positively associated with rates of social learning, and environmentally transmitted diseases were positively associated with rates of exploration. Because higher pathogen burdens can contribute to morbidity and mortality, we propose that parasitism is a significant cost associated with the behavioural patterns that underpin culture, and that increased pathogen exposure is likely to have played an important role in the evolution of culture in both non-human primates and humans.

Coinfection with Streptococcus pneumoniae negatively modulates the size and composition of the ongoing influenza-specific CD8⁺ T cell response.

Infection with influenza A virus can lead to increased susceptibility to subsequent bacterial infection, often with Streptococcus pneumoniae. Given the substantial modification of the lung environment that occurs following pathogen infection, there is significant potential for modulation of immune responses. In this study, we show that infection of mice with influenza virus, followed by the noninvasive EF3030 strain of Streptococcus pneumoniae, leads to a significant decrease in the virus-specific CD8(+) T cell response in the lung. Adoptive-transfer studies suggest that this reduction contributes to disease in coinfected animals. The reduced number of lung effector cells in coinfected animals was associated with increased death, as well as a reduction in cytokine production in surviving cells. Further, cells that retained the ability to produce IFN-γ exhibited a decreased potential for coproduction of TNF-α. Reduced cytokine production was directly correlated with a decrease in the level of mRNA. Negative regulation of cells in the mediastinal lymph node was minimal compared with that present in the lung, supporting a model of selective regulation in the tissue harboring high pathogen burden. These results show that entry of a coinfecting pathogen can have profound immunoregulatory effects on an ongoing immune response. Together, these findings reveal a novel dynamic interplay between concurrently infecting pathogens and the adaptive immune system.

Risk factors for moderate inflammation in Chinese adults with and without central obesity (370.1)

The relationship between lifestyle factors and inflammation varies by weight status. Whether the risk factors associated with inflammation differ with central obesity is less well understood, particularly in populations exposed to both the higher pathogen burdens and obesogenic behaviors associated with moderate elevations in C‐reactive protein (CRP). We examined the distribution of moderate inflammation (CRP 3‐10mg/L) with and without high waist circumference (WC) in 1190 adults participating in the China Health Nutrition Survey and tested whether the risk factors for inflammation differed between those with and without high WC. Men were less likely to have elevated CRP with high WC than women (43.9% vs. 72.3%, p&lt;0.001). In men, better household sanitation was associated with greater odds of elevated CRP with high WC (OR: 1.57, 95%CI: 1.21‐2.03). In women, post‐secondary education (OR: 0.27, 95%CI: 0.11‐0.62) and high fat‐ high energy diets (OR: 0.47, 95%CI: 0.25‐0.87) were associated with lower odds of elevated CRP with high WC. Similar results were seen in household‐level analyses controlling for spousal similarities in dietary and sanitation exposures. These results document different underlying risk factors for inflammation in Chinese men and women, suggesting that sex‐specific strategies may be needed to prevent and treat inflammation.Grant Funding Source: Supported by NIH NICHD (K01 HD071948‐01)

Association of cytomegalovirus and other pathogens with frailty and diabetes mellitus, but not with cardiovascular disease and mortality in psycho-geriatric patients; a prospective cohort study

BackgroundStudies about associations of infections with herpes viruses and other pathogens, such as Chlamydia pneumoniae (CP) and Helicobacter pylori (HP) with cardiovascular disease (CVD), diabetes mellitus (DM), frailty and/or mortality are conflicting. Since high levels of antibodies against these pathogens occur in the elderly, the role of these pathogens in morbidity and mortality of vulnerable elderly was explored.ResultsBlood samples of 295 community dwelling psycho-geriatric patients were tested for IgG antibodies to herpes simplex virus type 1 and 2, varicella zoster virus, Epstein Barr virus (EBV), cytomegalovirus (CMV), human herpes virus type 6 (HHV6), CP and HP. Frailty was defined with an easy-to-use previously described frailty risk score. Relative risks (RR) with 95% confidence intervals were calculated to evaluate associations between CVD, DM, frailty and pathogens. Pathogens as a predictor for subsequent mortality were tested using Kaplan Meier analyses and Cox proportional hazard models. The mean age was 78 (SD: 6.7) years, 20% died, 44% were defined as frail, 20% had DM and 49% had CVD. Presence of CMV antibody titers was associated with frailty, as shown by using both qualitative and quantitative tests, RR ratio 1.4 (95% CI: 1.003-2.16) and RR ratio 1.5 (95% CI: 1.06-2.30), respectively. High IgG antibody titers of HHV6 and EBV were associated with DM, RR ratio 3.3 (95% CI: 1.57-6.49). None of the single or combined pathogens were significantly associated with mortality and/or CVD.ConclusionsPrior CMV infection is associated with frailty, which could be in line with the concept that CMV might have an important role in immunosenescence, while high IgG titers of HHV6 and EBV are associated with DM. No association between a high pathogen burden and morbidity and/or mortality could be demonstrated.

Exhaustion, immuno-inflammation, and pathogen burden after cardiac surgery: An exploratory study

Exhaustion, a consequence of prolonged stress characterized by unusual fatigue, is associated with increased risk of cardiac morbidity and mortality. In patients recovering from coronary artery bypass (CABG), little is known about the relationship of 1) immune-mediated inflammation and resultant endothelial activation, and 2) cumulative exposure to infectious pathogens (pathogen burden (PB)) implicated in coronary atherosclerosis to exhaustion. The aim of this exploratory study was to investigate the association of PB, inflammatory markers (interleukin (IL)-6, IL-10) and a marker of endothelial activation (soluble intercellular adhesion molecule-1 (sICAM-1)) to exhaustion. One to two months post-CABG, 42 individuals who met inclusion criteria were assessed for exhaustion using the Maastricht Interview for Vital Exhaustion. Serum IgG antibodies to herpes simplex virus (HSV)-1, HSV-2, cytomegalovirus, Epstein Barr virus, and inflammatory and endothelial activation markers were measured by enzyme-linked immunosorbent assay. Pathogen burden was defined as the total number of seropositive exposures: low (0-1), moderate (2-3), and high (4). Prevalence of exhaustion was 40.5%. Relative to non-exhausted patients, exhausted patients demonstrated a higher frequency of moderate PB (h=0.73, p=0.04) but lower frequency of high PB (h=1.05, p=0.03). Exhaustion showed a non-significant trend for positive correlations with IL-6 and sICAM-1 levels, and inverse relation to PB. In subgroup analysis, exhausted patients had stronger correlations with IL-6 and IL-6:IL-10 and a tendency towards higher serum IL-10 concentrations compared with their non-exhausted counterparts. This hypothesis-generating study provides preliminary evidence that elevated post-CABG exhaustion may be associated with PB, inflammation, and endothelial activation.

Pathogenesis of the immune reconstitution inflammatory syndrome in HIV-infected patients

The immune reconstitution inflammatory syndrome (IRIS) is an important clinical complication in HIV-infected patients initiating antiretroviral therapy. This review focuses on the latest literature pertaining to the pathogenesis of IRIS. The clinical manifestations of IRIS are heterogeneous due to the variety of opportunistic infections that are associated with this inflammatory syndrome. However, the disproportionate inflammation is a defining hallmark for which common mechanisms are suspected. Lymphopenia-induced proliferation in the context of systemic immune activation, presence of high antigenic exposure and a wider availability of interleukin-7 contribute to the exacerbated immune response underlying IRIS. Defect in pathogen clearance by phagocytes might favor high pathogen burden, which in turn is thought to activate both innate immune cells and pathogen-specific T cells upon correction of the CD4 T-cell lymphopenia, predisposing to IRIS. This common scenario might be further invigorated by functional impairments among regulatory T cells. Further insight into the cellular mechanisms driving IRIS is urgently needed. Understanding the relative contribution of distinct effector and regulatory T-cell subsets, and innate immune components to IRIS is required to inspire future therapeutic approaches.

Altered Immune Response in Mice Deficient for the G Protein-coupled Receptor GPR34

The X-chromosomal GPR34 gene encodes an orphan G(i) protein-coupled receptor that is highly conserved among vertebrates. To evaluate the physiological relevance of GPR34, we generated a GPR34-deficient mouse line. GPR34-deficient mice were vital, reproduced normally, and showed no gross abnormalities in anatomical, histological, laboratory chemistry, or behavioral investigations under standard housing. Because GPR34 is highly expressed in mononuclear cells of the immune system, mice were specifically tested for altered functions of these cell types. Following immunization with methylated BSA, the number of granulocytes and macrophages in spleens was significantly lower in GPR34-deficient mice as in wild-type mice. GPR34-deficient mice showed significantly increased paw swelling in the delayed type hypersensitivity test and higher pathogen burden in extrapulmonary tissues after pulmonary infection with Cryptococcus neoformans compared with wild-type mice. The findings in delayed type hypersensitivity and infection tests were accompanied by significantly different basal and stimulated TNF-α, GM-CSF, and IFN-γ levels in GPR34-deficient animals. Our data point toward a functional role of GPR34 in the cellular response to immunological challenges.

Evaluation of the pathogenicity and virulence of three strains of Salmonella organisms in calves and pigs

To assess in pigs the pathogenicity and virulence of 3 strains of Salmonella spp capable of causing atypical salmonellosis in cattle. 36 Holstein calves and 72 pigs experimentally infected with Salmonella spp. Representative Salmonella strains associated with 3 new disease phenotypes (protozoa-mediated hypervirulence, multisystemic cytopathicity, and encephalopathy) that have been characterized in cattle during the past 10 years were orally inoculated into pigs. Clinical manifestations were compared with those observed in cattle. Samples were collected from various tissues, and the presence of Salmonella organisms was assessed qualitatively and quantitatively by use of Salmonella-selective media. Of the 3 unique Salmonella disease phenotypes observed in cattle, only protozoa-mediated hypervirulence was observed in pigs. Hypervirulence was related to a more rapid onset of disease and higher pathogen burden in pigs than in cattle. This phenotype was observed in pigs inoculated with multiresistant Salmonella enterica serotypes Typhimurium or Choleraesuis bearing the Salmonella genomic island 1 (SGI1) integron. Salmonella hypervirulence was identified in pigs noculated with SGI1-bearing strains exposed to free-living protozoa. Additionally, an SGI1-bearing strain of Salmonella Choleraesuis was detected that resulted in augmented virulence in pigs. Therefore, it appeared that protozoa-associated salmonellosis was analogous in pigs and cattle. Salmonella-mediated encephalopathy and multisystemic cytopathicity did not appear to be relevant diseases in pigs.

Th1 Cytokine Responses Fail to Effectively Control Chlamydia Lung Infection in ICOS Ligand Knockout Mice

ICOS ligand (ICOSL) plays an important role in controlling specific aspects of T cell activation, differentiation, and function. Th1-type immune responses have been shown to be critical in host defense against chlamydial infections. To assess the role of ICOSL-ICOS interaction in host defense against chlamydial infection, we compared the immune responses and pathological reactions in ICOSL gene knockout (KO) and wild-type (WT) mice following Chlamydia muridarum lung infection. The results showed that ICOSL KO mice exhibited greater body weight loss, higher pathogen burden, and more severe histopathology in their lung than did WT mice. Cytokine analysis revealed that ICOSL KO mice produced lower levels of Th2 (IL-4 and IL-5) and anti-inflammatory (TGF-beta1 and IL-10) cytokines, but higher Th1-related (IFN-gamma and IL-12p40/IL-23) and proinflammatory (IL-6 and TNF-alpha) cytokines. ICOSL KO mice also showed reduced Chlamydia-specific Ab levels in their sera and lung homogenates. In addition, ICOSL KO mice demonstrated significantly lower ICOS expression in T cells and lower Th17 responses than did WT mice. Finally, we showed that ICOS-ICOSL interaction and cell-cell contact are essential for CD4(+) T cells to inhibit chlamydial growth in the cultured lung fibroblasts. The data suggest that ICOSL plays a significant role in immunoregulation and protective immunity against Chlamydia infections and that the Th1 skew in cytokine responses per se is not sufficient for effective control of Chlamydia infections.

Expression Profiling the Temperature-Dependent Amphibian Response to Infection by Batrachochytrium dendrobatidis

Amphibians are experiencing a panzootic of unprecedented proportions caused by the emergence of Batrachochytrium dendrobatidis (Bd). However, all species are not equally at risk of infection, and risk is further modified by environmental variables, specifically temperature. In order to understand how, and when, hosts mount a response to Bd we analysed infection dynamics and patterns of gene expression in the model amphibian species Silurana (Xenopus) tropicalis. Mathematical modelling of infection dynamics demonstrate the existence of a temperature-dependent protective response that is largely independent of the intrinsic growth-rate of Bd. Using temporal expression-profiling by microarrays and qRT-PCR, we characterise this response in the main amphibian lymphoid tissue, the spleen. We demonstrate that clearance of Bd at the host-optimal temperature is not clearly associated with an adaptive immune response, but rather is correlated with the induction of components of host innate immunity including the expression of genes that are associated with the production of the antimicrobial skin peptide preprocareulein (PPCP) as well as inflammatory responses. We find that adaptive immunity appears to be lacking at host-optimal temperatures. This suggests that either Bd does not stimulate, or suppresses, adaptive immunity, or that trade-offs exist between innate and adaptive limbs of the amphibian immune system. At cold temperatures, S. tropicalis loses the ability to mount a PPCP-based innate response, and instead manifests a more pronounced inflammatory reaction that is characterised by the production of proteases and higher pathogen burdens. This study demonstrates the temperature-dependency of the amphibian response to infection by Bd and indicates the influence that changing climates may exert on the ectothermic host response to pathogens.

Cardiovascular disease prevalence and its relation to risk factors in Alaska Eskimos

Background and aims Although Eskimos were thought to be protected from cardiovascular disease (CVD), state health data show a large proportion of deaths from CVD, despite traditional lifestyles and high omega-3 fatty acid intake. This article explores CVD prevalence and its relation to risk factors in Alaska Eskimos. Methods and results A population-based cohort of 499 Alaska Eskimos > age 45 from the Norton Sound region was examined in 2000–2004 for CVD and associated risk factors as part of the Genetics of Coronary Artery Disease in Alaska Natives study. CVD and atherosclerosis were evaluated and adjudicated using standardized methods. Average age was 58 years; diabetes prevalence was low and high-density lipoprotein cholesterol (HDL-C) concentrations were high, but a large proportion smoked and had high pathogen burden. CVD was higher in men (12.6%) than in women (5.3%) (prevalence ratio 2.4, CI 1.3–4.4). Rates of stroke (6.1% in men, 1.8% in women) were similar to those for coronary heart disease (CHD) (6.1% men, 2.5% women). MI prevalence was low in both genders (1.9% and 0.7%). CVD was higher in men and in those >60 years. Hypertension, diabetes, high LDL-C, high apoB, and low HDL-C were all strong correlates (<.002) and albuminuria and CRP were also correlated with CVD ( p < .05) after adjustment for age and gender. Carotid atherosclerosis was correlated with CVD ( p = .0079) independent of other risk factors. Conclusion These data show high CHD and stroke prevalence in Alaska Eskimos, despite low average LDL-C and high HDL-C. Hypertension and high LDL-C were independent correlates; identifying these risk factors early and treating to target is recommended.

RP105 Facilitates Macrophage Activation by Mycobacterium tuberculosis Lipoproteins

RP105, phylogenetically related to Toll-like receptor (TLR)-4, is reported to facilitate B cell activation by the TLR4-agonist lipopolysaccharide (LPS)--but to limit LPS-induced cytokine production by antigen-presenting cells. Here, we show that the role of RP105 extends beyond LPS recognition and that RP105 positively regulates macrophage responses to Mycobacterium tuberculosis (Mtb) lipoproteins. Mtb-infected RP105(-/-) mice exhibited impaired proinflammatory cytokine responses associated with enhanced bacterial burden and increased lung pathology. The Mtb 19 kDa lipoprotein induced release of tumor necrosis factor in a manner dependent on both TLR2 and RP105, and macrophage activation by Mtb lacking mature lipoproteins was not RP105 dependent. Thus, mycobacterial lipoproteins are RP105 agonists. RP105 physically interacted with TLR2, and both RP105 and TLR2 were required for optimal macrophage activation by Mtb. Our data identify RP105 as an accessory molecule for TLR2, forming part of the receptor complex for innate immune recognition of mycobacterial lipoproteins.

Involvement of Toll-Like Receptor 2 in Experimental Invasive Pulmonary Aspergillosis

Aspergillus fumigatus, an opportunistic fungal pathogen, causes severe and usually fatal invasive pulmonary aspergillosis in immunocompromised hosts. Interestingly, Drosophila cells lacking the Toll protein are prone to A. fumigatus infection. In the current study, we looked for the involvement of Toll-like receptor 2 (TLR2) in the recognition of A. fumigatus by analyzing the in vivo and ex vivo responses of immunocompromised TLR2(-/-) and TLR2(+/+) mice to this fungus. Upon intratracheal administration of conidia, survival and tumor necrosis factor alpha (TNF-alpha), interleukin-12, and macrophage inhibitory protein-2 alpha concentrations in the airspaces of TLR2(-/-) mice were significantly lower than those of TLR2(+/+) animals. In vitro analysis of TNF-alpha production by conidia-challenged alveolar macrophages from TLR2(-/-) revealed a significant deficiency in comparison with macrophages from TLR2(+/+) mice. Infected TLR2(-/-) mice also have a higher respiratory distress and a higher pathogen burden than TLR2(+/+) mice. These data demonstrate that TLR2 plays a significant role in the defense of the host against A. fumigatus infection.

Impact of pathogen burden in patients with coronary artery disease in relation to systemic inflammation and variation in genes encoding cytokines

The number of infectious pathogens to which an individual has been exposed (pathogen burden) has been linked to the development and the prognosis of coronary artery disease (CAD). The interaction among infection, genetic host susceptibility, and CAD remains unclear. This study was aimed at evaluating the modulation of the association between CAD and pathogen burden, by serum levels of inflammatory markers and polymorphisms of the interleukin (IL)-6 and tumor necrosis factor (TNF)-α genes. Immmunoglobulin (Ig) G or IgA antibodies to 8 pathogens were determined in 991 patients with CAD and 333 control subjects. Serum levels of high-sensitivity C-reactive protein, fibrinogen, IL-6, and TNF-α were also measured. All subjects were genotyped for the IL-6/G-174C, the TNF/C-851T, and the TNF/G-308A polymorphisms. Analysis of single pathogens demonstrated a positive relation to the presence of CAD for some ( Chlamydia pneumoniae, cytomegalovirus, Helicobacter pylori, and herpes virus simplex type 1), but not all pathogens. A strong association between increasing pathogen burden and CAD was confirmed, even after adjustment for risk factors. The prevalence of a high pathogen burden (≥4 pathogens) was 50% in patients and 21% in controls (p <0.0001). A high pathogen burden was associated with decreased high-density lipoprotein cholesterol levels (p <0.001). The association between CAD and pathogen burden was modulated by the IL6/G-174C polymorphism, the odds ratio being higher in heterozygotes than in both types of homozygotes (p <0.05). This interaction appeared to be mediated by variations in serum IL-6 levels. No such interaction was detected with any of the 2 TNF-α polymorphisms.

Herpes viruses, cytokines, and altered hemostasis in vital exhaustion.

Infections with herpes viruses have been implicated in the pathogenesis of atherosclerosis. We tested the hypothesis that vital exhaustion (VE) is associated with multiple herpesvirus infections, such as herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, and cytomegalovirus, and with an increase in pathogen burden (ie, the aggregated seropositivity to immunoglobulin G antibodies for herpes simplex virus, varicella-zoster virus, Epstein-Barr virus, and cytomegalovirus). In addition, we examined the association of VE and pathogen burden with measures of hemostasis and inflammation. Blood samples were drawn from 29 men with VE and 30 male control subjects, all healthy and nonsmokers, to assess serological evidence of infection and measures of hemostasis and inflammation. VE is associated with a relatively high pathogen burden, altered hemostasis, and higher levels of cytokines, such as interleukin-6. Across all subjects, a relatively high pathogen burden was also associated with altered hemostasis but not with increased cytokine levels. The interaction of VE with pathogen burden revealed significant linear increases in measures of hemostasis and inflammation. Finally, immunoglobulin G antibody titer levels of individual herpesvirus infections were not associated with hemostatic measures or with cytokines. We conclude that stress-related alterations in hemostasis and inflammation are not necessarily linked to one particular herpesvirus infection but rather to an increase in aggregated seropositivity to herpesvirus infections.