Factors In Infectious Diseases Research Articles

Associations of diet with infectious diseases in UK Biobank.

This research aims to utilize multivariate logistic regression to explore associations between the frequency of 13 food groups intake (or four diet groups) and infectious diseases. 487849 participants from the UK Biobank were enrolled, and 75209 participants were diagnosed with infectious diseases. Participants reporting the highest intake frequency of processed meat [odds ratio ( OR) = 1.0964; 95% CI: 1.0622-1.1318] and red meat ( OR = 1.0895; 95% CI: 1.0563-1.1239) had a higher risk of infectious diseases compared to those with the lowest intake frequency. Consuming fish 2.0-2.9 times ( OR = 0.8221; 95% CI: 0.7955-0.8496), cheese ≥5.0 times ( OR = 0.8822; 95% CI: 0.8559-0.9092), fruit 3.0-3.9 servings ( OR = 0.8867; 95% CI: 0.8661-0.9078), and vegetables 2.0-2.9 servings ( OR = 0.9372; 95% CI: 0.9189-0.9559) per week were associated with a lower risk of infection. Low meat-eaters ( OR = 0.9404; 95% CI: 0.9243-0.9567), fish-eaters ( OR = 0.8391; 95% CI: 0.7887-0.8919), and vegetarians ( OR = 0.9154; 95% CI: 0.8561-0.9778) had a lower risk of infectious diseases compared to regular meat-eaters. Mediation analysis was performed, revealing glycosylated hemoglobin, white blood cell counts, and body mass index were mediators in the relationships between diet groups and infectious diseases. This study suggested that intake frequency of food groups is a factor in infectious diseases and fish-eaters have a lower risk of infection.

Time to Positivity in Blood Culture Bottles Inoculated with Sonication Fluid from Fracture-Related Infections.

The timely and accurate identification of causative agents is crucial for effectively managing fracture-related infections (FRIs). Among various diagnostic methods, the "time to positivity" (TTP) of cultures has emerged as a valuable predictive factor in infectious diseases. While sonication of implants and inoculation of blood culture bottles with sonication fluid have enhanced sensitivity, data on the TTP of this microbiological technique remain limited. Therefore, patients with ICM criteria for confirmed FRI treated at our institution between March 2019 and March 2023 were retrospectively identified and their microbiological records were analyzed. The primary outcome parameter was TTP for different microorganism species cultured in a liquid culture collected from patients with confirmed FRI. A total of 155 sonication fluid samples from 126 patients (average age 57.0 ± 17.4 years, 68.3% males) was analyzed. Positive bacterial detection was observed in 78.7% (122/155) of the liquid culture pairs infused with sonication fluid. Staphylococcus aureus was the most prevalent organism (42.6%). Streptococcus species exhibited the fastest TTP (median 11.9 h), followed by Staphylococcus aureus (median 12.1 h) and Gram-negative bacteria (median 12.5 h), all of which had a 100% detection rate within 48 h after inoculation. Since all Gram-negative pathogens yielded positive culture results within 24 h, it could be discussed if empirical antibiotic therapy could be de-escalated early and limited towards the Gram-positive germ spectrum if no Gram-negative pathogens are detected up to this time point in the context of antibiotic stewardship.

Miana (Coleus scutellariodes) Inhibits Nuclear Factor-kappa B (NF-kB) Activity and its Antibacterial and Anti-inflammatory Benefits in Infectious Diseases: Review Article

Background: Miana, also known as Coleus scutellariodes, is a supplement agent frequently used to treat infectious disorders. Its antibacterial and anti-inflammatory mechanisms are not well understood. Nuclear factor-kappa B (NF-kB), which acts as a major regulator in these infectious processes, strongly induces proinflammatory cytokines via I-kB through its connection with the NF-kB receptor, which affects cytokine production, and angiogenesis via the role of VEGF and HIF-1. VEGF is an angiogenic factor that can trigger cellular responses on the surface of endothelial cells via the NF-kB pathway. HIF-1 has a critical role in the cellular response to systemic oxygen levels of cells. This article's objective is to provide a thorough analysis of molecular mechanisms of NF-kB in relation to infectious diseases treated by Miana. Methods: To obtain the data for this study, relevant reference lists were manually searched in the PubMed, EMBASE, and Scopus databases using the keywords "Miana", "Coleus scutellariodes", "NF-kB", "antibacterial", "anti-inflammation" and "Infectious diseases." as significant reference lists. This review article included and narratively covered each appropriate article from the database above. Results: It was found in several articles that NF-kB and molecular mechanisms of Miana in infectious diseases are strongly related, and that these mechanisms may be used to cure and prevent infectious diseases. The molecular mechanism of Miana containing the active component of flavonoids is broad and complex, in which the induced NF-kB has two main pathways, namely canonical and non-canonical initially from the upstream and downstream of NF-kB activities and there is intricate crosstalk of NF-kB. Conclusions: Miana treats infectious diseases through NF-kB, which functions mainly through a variety of mechanisms. Miana's treatment of infectious diseases with NF-kB leads to the conclusion that NF-kB is a stimulator of several proinflammatory cytokines. Additionally, Miana can reduce HIF-1 expression, and HIF-1 is also in function of upregulating some angiogenic factors in infectious diseases, therefore Miana may suppress NF-kB activities both in vitro and in vivo. Miana contains an active component of flavonoid, which has broad capabilities in both inflammatory and non-inflammatory processes, thus research is urgently needed that links from upstream to downstream of its molecular mechanisms. Besides that, a more detailed study is needed on the intricate crosstalk in the inflammatory process due to microorganism infection through NF-kB activity in Miana interventions containing flavonoid active substances.

A compelling demonstration of why traditional statistical regression models cannot be used to identify risk factors from case data on infectious diseases: a simulation study

BackgroundRegression models are often used to explain the relative risk of infectious diseases among groups. For example, overrepresentation of immigrants among COVID-19 cases has been found in multiple countries. Several studies apply regression models to investigate whether different risk factors can explain this overrepresentation among immigrants without considering dependence between the cases.MethodsWe study the appropriateness of traditional statistical regression methods for identifying risk factors for infectious diseases, by a simulation study. We model infectious disease spread by a simple, population-structured version of an SIR (susceptible-infected-recovered)-model, which is one of the most famous and well-established models for infectious disease spread. The population is thus divided into different sub-groups. We vary the contact structure between the sub-groups of the population. We analyse the relation between individual-level risk of infection and group-level relative risk. We analyse whether Poisson regression estimators can capture the true, underlying parameters of transmission. We assess both the quantitative and qualitative accuracy of the estimated regression coefficients.ResultsWe illustrate that there is no clear relationship between differences in individual characteristics and group-level overrepresentation —small differences on the individual level can result in arbitrarily high overrepresentation. We demonstrate that individual risk of infection cannot be properly defined without simultaneous specification of the infection level of the population. We argue that the estimated regression coefficients are not interpretable and show that it is not possible to adjust for other variables by standard regression methods. Finally, we illustrate that regression models can result in the significance of variables unrelated to infection risk in the constructed simulation example (e.g. ethnicity), particularly when a large proportion of contacts is within the same group.ConclusionsTraditional regression models which are valid for modelling risk between groups for non-communicable diseases are not valid for infectious diseases. By applying such methods to identify risk factors of infectious diseases, one risks ending up with wrong conclusions. Output from such analyses should therefore be treated with great caution.

Tetraspanins: Host Factors in Viral Infections.

Tetraspanins are transmembrane glycoproteins that have been shown increasing interest as host factors in infectious diseases. In particular, they were implicated in the pathogenesis of both non-enveloped (human papillomavirus (HPV)) and enveloped (human immunodeficiency virus (HIV), Zika, influenza A virus, (IAV), and coronavirus) viruses through multiple stages of infection, from the initial cell membrane attachment to the syncytium formation and viral particle release. However, the mechanisms by which different tetraspanins mediate their effects vary. This review aimed to compare and contrast the role of tetraspanins in the life cycles of HPV, HIV, Zika, IAV, and coronavirus viruses, which cause the most significant health and economic burdens to society. In doing so, a better understanding of the relative contribution of tetraspanins in virus infection will allow for a more targeted approach in the treatment of these diseases.

Effect of daily human movement on some characteristics of dengue dynamics

Human movement is a key factor in infectious diseases spread such as dengue. Here, we explore a mathematical modeling approach based on a system of ordinary differential equations to study the effect of human movement on characteristics of dengue dynamics such as the existence of endemic equilibria, and the start, duration, and amplitude of the outbreak. The model considers that every day is divided into two periods: high-activity and low-activity. Periodic human movement between patches occurs in discrete times. Based on numerical simulations, we show unexpected scenarios such as the disease extinction in regions where the local basic reproductive number is greater than 1. In the same way, we obtain scenarios where outbreaks appear despite the fact that the local basic reproductive numbers in these regions are less than 1 and the outbreak size depends on the length of high-activity and low-activity periods.

Pyroptotic cell-derived microparticle: An atherogenic factor in infectious diseases

Chronic infection is considered a risk factor for atherosclerosis. The link between infectious agents and atherosclerosis is manifested by the presence of infection-induced pyroptotic cells in atherosclerotic lesions. Pyroptosis is an inflammatory form of programmed cell death that occurs most frequently upon infection. However, inflammation is not the only cause by which pyroptosis involved in atherosclerosis. During pyroptosis, a large amount of microparticles are released from pyroptotic cells, which not only transfer inflammatory mediators to arterial vessel, but also mediate the interaction between a variety of cells, leading to endothelial injury, macrophage infiltration, vascular smooth muscle cell migration and proliferation, thereby accelerating atherosclerosis. Thus, we proposed hypothesis that pyroptotic cell-derived microparticle is an atherogenic factor in infectious diseases.

Profile of HIV Inpatients, Mortality Rate and Associated Factors in the Era of Antiretroviral Therapy at an Urban Hospital in Burkina Faso

Background: HIV infection remains a public health concern mainly in infectious diseases department despite the availability of diagnosis and antiretroviral therapy. Our objectives were to describe the clinical and biological profiles of HIV inpatients and to determine mortality rate and associated factors in infectious diseases department among these patients. Method: Retrospective cross-sectional study using medical records from January, the 1rst 2011 to December, the 31th 2015 is conducted at an urban teaching hospital in Burkina Faso (Bobo-Dioulasso town). The study included patients over 15 years tested HIV-positive and hospitalized in the department of infectious diseases during the period of the study. Usual statistic was performing to describe study population and logistic regression to identify factors associated with death. Result: A total of 730 medical records were included of which 440 inpatients were women with a sex-ratio of 0.6.Their average age were 40.3± 10.7 years-old. The three and four clinical stages according to the World health organization (WHO) classification were dominant with 37.1% and 56.9% respectively.The average of CD4 cell counts was 133.96 cell/µL and 79% of patients had less than 200 CD4 cell/µL. The main diagnoses were: tuberculosis (20.7%), gastroenteritis (19.3%) and bacterial pneumonia (15.7%). Before hospitalization, 40.9% of the patients were treated with antiretroviral therapy. The ARV treatment was started during hospitalization for 8% of the HIV infected patients without ARV treatment at entry, and for 2.8% of patient’s detected HIV positive during the hospitalization. The overall mortality rate was 33.4%. By multivariate analysis, the factors associated to death in the study period were: general state at the input, age group, duration of hospitalization and presence of secondary diagnosis. Conclusion: HIV-related infections are the main causes of hospitalization in our service. The mortality rate among HIV inpatients stayed high. Improvements of HIV inpatients health care management would be needed.

Hospitalisations for mycoses as an indicator of socio-environmental vulnerability in the Brazilian Amazon-Savanna transition region.

The infections caused by fungi represent a global concern and an important cause of hospital admissions in endemic areas. The influence of socio-environmental factors in infectious diseases has been documented; however, this phenomenon remains unclear regarding mycoses. This study aimed to analyse the spatio-temporal dynamics of hospitalisations for mycoses (HM) and the association with socio-economic and climate data in the Amazon-Savanna Transition Region in the state of Maranhão, Brazil. In this study, Spearman's correlation was applied to determine the correlation between HM, socio-economic and climatic data obtained from national databases in the period from 1998 to 2016. Hospitalisations for mycoses data were spatialised and analysed using the local Moran's index. Our data revealed a negative and significant correlation between HM and socio-economic data regarding population, demographic density, human development index, health facilities and sanitary sewage. Significant correlations were observed between HM and precipitation, maximum temperature and minimum temperature. The main modulating climatic variable was the minimum temperature. The spatial autocorrelation analysis showed the dynamics of HM in municipalities belonging to the different regions of the state influenced by socio-economic conditions. We observed the presence of municipalities with high incidence of HM surrounded by others with low HM cases and vice versa. Our results indicate that hospitalisations for mycoses represent an important indicator of socio-environmental vulnerability in the Amazon-Savanna transition region in Brazil. We encourage the adoption of measures to mitigate social and environmental impact on these diseases, especially in municipalities with low socio-economic status.

Needle and Syringe Programs in Rural Areas: Addressing the Intravenous Drug Use Epidemic

BackgroundOpioid use has reached epidemic proportions in rural communities in the United States and injection of drugs is commonly used. As a result of shared or reusing needles and syringes, the risk for contracting blood-borne diseases is significantly increased. Rural areas face many social and attitudinal barriers regarding syringe exchange programs (SEPs).ObjectiveThis article describes national trends for drug injection problems in rural areas and discusses effectiveness of needle and SEPs as a harm reduction healthcare policy. Ethical and practical considerations in the implementation of SEPs are also presented.MethodThe rehabilitation literature was reviewed on trends in substance abuse and intravenous (IV) drug use in rural areas to identify the status and need for SEPs to address risk factors of infectious diseases resulting from needle sharing and reusing of needles.FindingsIV drug use in rural communities has reached epidemic proportions with resulting dramatic increases in hepatitis C and B and incidence of HIV. Yet, many rural communities continue to object to the implementation of SEPs due to fears that such programs will increase drug use and crime in the community.ConclusionIV drug use is a critical public health issue for users and non-IV users in rural communities, and is increasingly becoming an issue about which rural rehabilitation counselors will need to be informed. For the sake of public health, SEPs should be recognized as an economical, ethical, and effective factor in the larger response to the epidemic of IV drug use in rural America.

Mycobacterium tuberculosis Prolyl Oligopeptidase Induces In vitro Secretion of Proinflammatory Cytokines by Peritoneal Macrophages.

Tuberculosis (TB) is a disease that leads to death over 1 million people per year worldwide and the biological mediators of this pathology are poorly established, preventing the implementation of effective therapies to improve outcomes in TB. Host–bacterium interaction is a key step to TB establishment and the proteases produced by these microorganisms seem to facilitate bacteria invasion, migration and host immune response evasion. We presented, for the first time, the identification, biochemical characterization, molecular dynamics (MDs) and immunomodulatory properties of a prolyl oligopeptidase (POP) from Mycobacterium tuberculosis (POPMt). POP is a serine protease that hydrolyzes substrates with high specificity for proline residues and has already been characterized as virulence factor in infectious diseases. POPMt reveals catalytic activity upon N-Suc-Gly-Pro-Leu-Gly-Pro-AMC, a recognized POP substrate, with optimal activity at pH 7.5 and 37°C. The enzyme presents KM and Kcat/KM values of 108 μM and 21.838 mM-1 s-1, respectively. MDs showed that POPMt structure is similar to that of others POPs, which consists of a cylindrical architecture divided into an α/β hydrolase catalytic domain and a β-propeller domain. Finally, POPMt was capable of triggering in vitro secretion of proinflammatory cytokines by peritoneal macrophages, an event dependent on POPMt intact structure. Our data suggests that POPMt may contribute to an inflammatory response during M. tuberculosis infection.

Lipoproteins attenuate TLR2 and TLR4 activation by bacteria and bacterial ligands with differences in affinity and kinetics.

BackgroundThe small intestine is a specialized compartment were close interactions take place between host, microbes, food antigens and dietary fatty acids. Dietary fats get absorbed by epithelial cells and processed into a range of lipoprotein particles after which they are basolaterally secreted and collected in the lymphatics. In contrast to the colon, the small intestine is covered only by a thin mucus coat that allows for intimate interactions between host-cells and microbes. Lipoproteins have long been recognized as protective factors in infectious diseases via the neutralization of bacterial toxins like lipopolysaccharides. Much less attention has been given to the potential role of lipoproteins as factors contributing to the maintenance of small intestinal immune homeostasis via modulating bacteria-induced immune responses.ResultsLipoproteins VLDL, LDL and HDL were found to neutralize TLR responses towards specific TLR-ligands or a selection of gram-negative and gram-positive bacteria. Attenuation of TLR2 activity was acute and only slightly improved by longer pre-incubation times of ligands and lipoproteins with no differences between bacterial-lipopeptides or bacteria. In contrast, attenuation of TLR4 responses was only observed after extensive preincubation of lipoproteins and LPS. Preincubation of bacteria and lipoproteins led only to a modest attenuation of TLR4 activity. Moreover, compared to TLR2, TLR4 activity could only be attenuated by lipoproteins over a small ligand dose range.ConclusionsThese results demonstrate the ability of lipoproteins VLDL, LDL and HDL to inhibit TLR responses towards bacterial-ligands and bacteria. Presence of lipoproteins was found to modulate the MAMP-induced cytokine release by primary human monocytes measured as changes in the release of IL-6, TNFα, GM-CSF and IFNγ. Using TLR2 and TLR4-reporter cells, lipoproteins were found to inhibit TLR responses with differences in affinity and kinetics. These data establish a role for lipoproteins as immunoregulatory molecules, attenuating TLR-responses and thereby positively contributing to mucosal homeostasis.Electronic supplementary materialThe online version of this article (doi:10.1186/s12865-016-0180-x) contains supplementary material, which is available to authorized users.

Applied research for better disease prevention and control.

In 1976, two years before the Alma Ata Declaration, the then Director-General of WHO, Dr. Halfdan Mahler, proclaimed a “social revolution in public health” [1]. He saw the establishment of the Special Programme for Research and Training in Tropical Diseases (TDR) Programme in 1975 as playing an active part in the emerging social and health development agenda. In TDR's first public document, Mahler, and his UNDP counterpart Morse stated: “Many millions of the people living in the tropical regions of the world are cut off from the mainstream of social and economic progress. Victims of a heavy burden of disease as well as of harsh economic circumstances, they are not free to choose and plan a better future… Health and development are therefore inextricably interlinked and any strategy for improvement must be based upon this reality” [2]. In these early years of “international” health, it became increasingly apparent that the development of new health technologies was only one component of improved healthcare. Research was required to support the delivery of those technologies, as well as to understand the barriers that could prevent or limit access to them. TDR was one of the first United Nations co-sponsored programmes to recognize this need. From 1977 onward, it had a dedicated focus on applied social and economic research and produced a body of evidence that promoted and expanded the theoretical underpinnings of this field, supported training in low- and middle-income countries where the needs existed, and developed a research agenda and funding to specifically address the “social and economic factors that affect the transmission and control of disease… and to increase the effectiveness of disease control programmes by integrating human behavioural (social, cultural, and economic) factors in programme conception, design, and management” [3], [4]. In its first phase, research investigated human behaviour related to disease exposure, disease-related beliefs and attitudes, attitudes to disease control, the social and economic impact of tropical diseases, costs and effectiveness of alternative disease control measures, and economic development and disease [5]. It focused on the development of theory and methods for applying the social sciences in public health, community participation in disease control, and the economics of tropical diseases [6]. A later emphasis on the “upstream” factors in infectious diseases and their control, from 2000 to 2007, drew from basic social sciences and their subdisciplines, e.g., (medical) anthropology, (health) economics, (medical) sociology, political sciences, and health policy research [7]. Research focused on equity and access, health sector reform, community participation, gender-sensitive interventions [8], [9], globalization, human rights [10], and ethics [11], [12]. TDR also defined and exemplified the concept of applied social sciences for public health (ASSPH) [13], [14] and called for increasing the numbers of scientists trained in these areas. It identified implementation research as a critical aid to help disease control programmes, citing an “absence of capacity and understanding in how to engage with communities and ensure their participation, and of the ability to adapt research methods and health technologies to local contexts,” concluding that “the uptake, effectiveness, and sustainability of these interventions remains limited” [15]. Later, TDR led efforts to define and establish operational and implementation research as scholarly fields [16], [17]. Operational research was defined as “research into strategies, interventions, tools, or knowledge that can enhance the quality, coverage, effectiveness, or performance” of health systems or disease programmes [18]. Implementation research pursues research into the delivery of efficient, sustainable, and effective services; appropriate structure of health systems; the policy process; and other components that are necessary to bring new and old control interventions into the routine practice of national health systems and improve access particularly for vulnerable population groups. Both types of research are complementary [19].

The trend in distribution of Q223R mutation of leptin receptor gene in amoebic liver abscess patients from North India: a prospective study.

Host genetic susceptibility is an important risk factor in infectious diseases. We explored the distribution of Q223R mutation in leptin receptor gene of amoebic liver abscess (ALA) patients of North India. A total of 55 ALA samples along with 102 controls were subjected to PCR-RFLP analysis. The frequency of allele “G” (coding for arginine) was in general high in Indian population irrespective of the disease. Our results of Fisher exact test shows that heterozygous mutant (QQ versus QR, P = 0.049) and homozygous mutant (QQ versus RR, P = 0.004) were significantly associated with amoebic liver abscess when compared with homozygous wild (QQ).

Trapped intermediates in crystals of the FMN-dependent oxidase PhzG provide insight into the final steps of phenazine biosynthesis

Phenazines are redox-active secondary metabolites that many bacteria produce and secrete into the environment. They are broad-specificity antibiotics, but also act as virulence and survival factors in infectious diseases. Phenazines are derived from chorismic acid, but important details of their biosynthesis are still unclear. For example, three two-electron oxidations seem to be necessary in the final steps of the pathway, while only one oxidase, the FMN-dependent PhzG, is conserved in the phenazine-biosynthesis phz operon. Here, crystal structures of PhzG from Pseudomonas fluorescens 2-79 and from Burkholderia lata 383 in complex with excess FMN and with the phenazine-biosynthesis intermediates hexahydrophenazine-1,6-dicarboxylate and tetrahydrophenazine-1-carboxylate generated in situ are reported. Corroborated with biochemical data, these complexes demonstrate that PhzG is the terminal enzyme in phenazine biosynthesis and that its relaxed substrate specificity lets it participate in the generation of both phenazine-1,6-dicarboxylic acid (PDC) and phenazine-1-carboxylic acid (PCA). This suggests that competition between flavin-dependent oxidations through PhzG and spontaneous oxidative decarboxylations determines the ratio of PDC, PCA and unsubstituted phenazine as the products of phenazine biosynthesis. Further, the results indicate that PhzG synthesizes phenazines in their reduced form. These reduced molecules, and not the fully aromatized derivatives, are the likely end products in vivo, explaining why only one oxidase is required in the phenazine-biosynthesis pathway.

359 HLA FOOTPRINTS IN HIV/HCV CO-INFECTED PATIENTS

Background and Aims: HLA-diversity is a major host genetic risk factor in infectious diseases. In particular, several studies have described associations between distinct HLA alleles and outcomes of HCV and HIV infection. The objective of this study was to analyse the distribution of HLA Class I alleles in HIV/HCV co-infected individuals in order to identify HLA-disease associations that reflect the impact of this dual infection. Methods: Clinical data from 1110 Caucasian patients (HCV: n =477, HIV: n =181, HIV and HCV: n =346, healthy controls: n = 106) were retrieved by retrospective chart review. HLA-A and B allele distribution were determined by molecular methods (SSO and SSP) with HLA-resolution reduced to the 2-digit level to enable uniform comparisons. Fisher’s exact test and Chi-square tests with Yates correction for multiple testing were applied for statistical analysis. Results: Patients with HCV mono-infection were significantly older than patients in each other group (p < 0.001). MSM was the predominant risk factor for HIV infection (52%), while most HIV/HCV and HCV-infected patients had been infected via blood exposure (83%). The frequency of HLA alleles HLA-A*30 (p =0.023), HLA-B*08 (p =0.003), HLA-B*39 (p =0.003), and HLAB*49 (p =0.032) did not differ between the patient groups but was significantly reduced in infected patients as compared to healthy controls irrespective from the underlying type of infection. In contrast, HLA-B*57, which is assumed to increase chances of spontaneous HCV resolution and delay HIV progression, was selectively increased in patients with HIV mono-infection (13%) as compared to each other group (healthy controls: 9%, HIV/HCV and HCV mono-infection: 6% each; p =0.022). Conclusion: Reduced detection rates in HIVor HCV-monoand HIV/HCV co-infected patients indicate that alleles HLA-A*30, HLAB*08, HLA-B*39, and HLA-B*49 carry a poor prognosis but do not reflect interactions between HIVand HCV-infections. Patients with blood-borne infections usually acquire HCV first and HIV later on. Thus, finding a high HLA-B57 carrier rate in HIV+ patients but in none of the other groups indicates a protective role of this allele for both HIV and HCV infection. Taken together long-term exposure of Caucasian patients to HIV and HCV infection seems to induce subtle footprints in their HLA class I repertoire.

360 CXCL10 GENE POLYMORPHISM PREDICTS RAPID VIROLOGIC RESPONSE TO PEGYLATED INTERFERON/RIBAVIRIN COMBINATION THERAPY IN ASIAN PATIENTS WITH DIFFICULT-TO-TREAT CHRONIC HEPATITIS C GENOTYPE

Background and Aims: HLA-diversity is a major host genetic risk factor in infectious diseases. In particular, several studies have described associations between distinct HLA alleles and outcomes of HCV and HIV infection. The objective of this study was to analyse the distribution of HLA Class I alleles in HIV/HCV co-infected individuals in order to identify HLA-disease associations that reflect the impact of this dual infection. Methods: Clinical data from 1110 Caucasian patients (HCV: n =477, HIV: n =181, HIV and HCV: n =346, healthy controls: n = 106) were retrieved by retrospective chart review. HLA-A and B allele distribution were determined by molecular methods (SSO and SSP) with HLA-resolution reduced to the 2-digit level to enable uniform comparisons. Fisher’s exact test and Chi-square tests with Yates correction for multiple testing were applied for statistical analysis. Results: Patients with HCV mono-infection were significantly older than patients in each other group (p < 0.001). MSM was the predominant risk factor for HIV infection (52%), while most HIV/HCV and HCV-infected patients had been infected via blood exposure (83%). The frequency of HLA alleles HLA-A*30 (p =0.023), HLA-B*08 (p =0.003), HLA-B*39 (p =0.003), and HLAB*49 (p =0.032) did not differ between the patient groups but was significantly reduced in infected patients as compared to healthy controls irrespective from the underlying type of infection. In contrast, HLA-B*57, which is assumed to increase chances of spontaneous HCV resolution and delay HIV progression, was selectively increased in patients with HIV mono-infection (13%) as compared to each other group (healthy controls: 9%, HIV/HCV and HCV mono-infection: 6% each; p =0.022). Conclusion: Reduced detection rates in HIVor HCV-monoand HIV/HCV co-infected patients indicate that alleles HLA-A*30, HLAB*08, HLA-B*39, and HLA-B*49 carry a poor prognosis but do not reflect interactions between HIVand HCV-infections. Patients with blood-borne infections usually acquire HCV first and HIV later on. Thus, finding a high HLA-B57 carrier rate in HIV+ patients but in none of the other groups indicates a protective role of this allele for both HIV and HCV infection. Taken together long-term exposure of Caucasian patients to HIV and HCV infection seems to induce subtle footprints in their HLA class I repertoire.

In Vitro Reconstitution of a Bacterial Polysaccharide Biosynthetic Pathway

Bacterial polysaccharides represent an important pathogenic factor in infectious diseases. However, the complexity of these molecules has hampered efforts to delineate their biosynthesis. In our research, we chemo‐enzymatically synthesize O86 O‐unit (RU‐PP‐Und). We carried out an in vitro reaction to probe polymerization using 3H‐labelled RU‐PP‐Und and partially purified polymerase Wzy. The paper chromatography result demonstrated the formation of higher molecular weight compounds in the presence of Wzy. The radioactive signal on the SDS‐PAGE gel gave a ladder‐like pattern consistent with the formation of multiple repeating units. It is thus evident that repeating unit polymerization has been successfully reconstituted in vitro. We also introduced purified Wzz proteins obtained from two different E. coli O86 strains (B7 and H2) into the polymerization system. Our results demonstrate the in vitro generation of polysaccharides with appropriate chain length modalities through use of purified Wzz proteins. We prepared analogs derived from various lipids. The results indicate that double bond geometry holds more importance in determining the efficiency of polymerization. In conclusion, we have demonstrated the use of a reconstitution system to not only enable the in vitro production of polysaccharides, but also allow for generation of different chain length modalities. This system has provided the groundwork necessary for further underpinning the molecular details of the wzy‐dependent pathway. This research is supported by NCI (R01 CA118208), NIH (R01 GM085267), NSF (CHE‐0616892) and Bill &amp; Melinda Gates Foundation (51946) for financial support.

Microbial proteinase inside human cells as anti-mitochondrial activity: A new virulence factor in infectious diseases?

Both bacteria and fungi produce extracellular proteinases since they need aminoacids for optimal reproduction. This may also occur inside host cells. Viral proteinases are produced during propagation inside host cells to supply amino acids for rapid synthesis of viral proteins, and/or to split poly-protein molecules into single protein molecules, e.g., capside, and matrix and/or envelope proteins.In host cells the most profound, microbial proteinase-mediated effect is thought to be damage of the mitochondria, the site of oxidative energy generation. Two major effects can be imagined: (i) damage of proteinase-susceptible extra-mitochondrial membrane-associated proteins (razor blade effect), e.g., of mitochondrial transport proteins and of ATP:ADP translocase, and (ii) damage of intra-mitochondrial proteinase-susceptible proteins that are involved in the energy-generating processes. Although proteinases are not thought to invade and destroy mitochondria and essential intra-mitochondrial structures involved in energy generation, they can destroy non-mitochondrial encoded mitochondrial proteins during transport to the mitochondria, i.e., before incorporation inside the mitochondria in intra-mitochondrial structures.A secondary effect may be damage of liver cells that effect hepatic gluconeogenesis, the process that is involved in the synthesis of glucose from lactic acid. The proteinase may bring about inactivation of specific gluconeogenesis enzymes. This means that accumulated amounts of lactic acid cannot rapidly be reduced and consequently, such inactivation will increase intracellular and later even systemic acidification that may finally result in death.We postulate that both direct and indirect proteinase-mediated damage of mitochondria and gluconeogenesis enzymes, and consequently of human cellular energy generation, is an essential element in acute (e.g., influenza) and chronic (e.g., hepatitis B) intracellular infections.

Production of chemotactic factors in infectious diseases of the nervous system

Production of chemotactic factors in infectious diseases of the nervous system