Course Of Primary Infection Research Articles

Oral diseases in patients infected with HIV

Introduction: In recent years, more and more people have become infected with Human Immunodeficiency Virus. Of great importance in the course of HIV infection are symptoms and diseases, which often occurs in the oral cavity with a corresponding decrease in lymphocytes.Aim: The aim of the study was the study was to present the most common oral diseases in patients infected with Human Immunodeficiency Virus like hairy leukoplakia, Candidas, angular cheilitis, Linear Gingival Erythema, Herpesviridae virus infections, ulcerative lesions or xerostomia.Description: Clinicians should pay attention to oral manifestation of HIV infections because it may speed up the diagnostics process and may allow better control of the course of the infection. Hairy leukoplakia related to EBV is a marker of HIV on the side border of the tongue and appears as a hyperkeratotic stripes. Candidiasis may occur in many forms as acute pseudomembranous candidiasis, acute erythematous candidiasis, hyperplastic candidiasis or Median Rhomboid Glossitis. The most common fungus is Candida albicans but there may also be Candida krusei, Candida glabrata or Candida tropicalis. Another disease is Angular Cheilitis which is an inflammatory process localized in the commissure of the labia and can be caused by vitamin B deficiency, Candida, Staphylococcus or Streptococcus infection. Linear Gingival Erythema is a red linear lesion on the gingival margin infiltrated by polynuclear leukocytes and plasma cells. Patients with HIV also present Herpesviridae infections symptoms, ulcerations. Summary: This review shows that HIV/AIDS patients should be monitored for oral manifestation of the HIV infection and weakened immune system. Diseases described in this study are reliable markers of the HIV infection and clinicians should pay attention to them to monitor the course of primary infection.

Outcome of Chlamydia muridarum genital infection and immune response in a beta2-adrenergic receptor knockout stress mouse model

Abstract The beta-2-adrenergic receptor (β2-AR) is one of the β-AR subsets found in most immune cells and is stimulated by norepinephrine (NE) binding. We showed previously that exposure of a mouse model to cold water stress leads to high level production of NE that may result in increased intensity of Chlamydia muridarum genital infection but the mechanism is not well defined. The purpose of this study was to develop and characterize a β2-AR knockout (KO) stress mouse model to investigate its susceptibility to C. muridarum genital infection. We hypothesized that lacking the β2-AR leads to a decreased C. muridarum shedding from the genital tract of stressed mice compared to that of stressed wild type (WT) mice. Stressed and non-stressed C57BL/6J WT and β2-AR KO mice were infected intravaginally with C. muridarum. Swabbing at 3-day intervals during primary infection and C. muridarum isolation was performed by culturing in McCoy tissue culture following standard methods. β2-AR KO stressed mice had a mean of 8540 inclusion forming units/ml (IFU/ml) compared to a mean of 18000 IFU/ml of stressed wild type at day 9 post infection. The overall course of primary infection in the β2-AR KO mouse model showed slightly reduced Chlamydia shedding. In addition, transfer of CD4+ T cells from black J6 WT to β2-AR KO resulted in a significant increase of shedding compared to that of non-stressed WT transfer (6000 versus 1000 IFU/ml). Secretion of interferon gamma was restored in β2-AR KO mice compared to WT. Overall, these results imply that deficiency in β2-AR leads to decreased C. muridarum shedding compared to the WT. However, other members of the alpha- and beta-adrenergic receptor family may compensate for the absence in β2-AR KO mice thus more investigation is needed.

Spatial and temporal evolution of lung granulomas in a cynomolgus macaque model of Mycobacterium tuberculosis infection

BackgroundLittle is known about granuloma progression of Mycobacterium tuberculosis infection in humans. Using serial positron emission tomography and computed tomography (PET/CT) of an animal model that recapitulates human infection with M. tuberculosis, we are able to track lung granulomas. ObjectiveWe characterized the spatial and temporal pattern of granuloma formation during primary infection and reactivation. MethodsSerial PET/CT was performed on cynomolgus macaques (n = 28) during primary and reactivation M. tuberculosis infection. Distances between granulomas during the first six weeks post infection (“primary” granulomas) were compared to new granulomas that developed afterwards (“secondary” granulomas) using nearest neighbor analysis during primary infection, reactivation and between different routes of infection. ResultsSecondary granulomas developed within 2 cm of a primary granuloma within the same lung lobe with 80% probability during the course of primary infection, and this same pattern was observed during reactivation of latent infection after immune suppression. Using a logistic growth function, we were able to predict the maximum number of granulomas that would develop over the course of infection with good correlation (R2 = 0.96). ConclusionThese data provide important insights into the dynamic patterns of bacterial dissemination during the earliest phases of primary infection and reactivation tuberculosis.

Seminal vesicle fluid increases the efficacy of intravaginal HSV-2 vaccination.

Once considered merely as a vehicle for spermatozoa, it is now clear that seminal plasma (SP) induces a variety of biological actions on the female reproductive tissues able to modulate the immune response against paternal antigens. To our knowledge, the influence of SP on the immune response against sexually transmitted pathogens has not been yet evaluated. We here analyzed whether the seminal vesicle fluid (SVF), which contributes almost 60% of the SP volume in mice, could modulate the immune response against herpes simplex virus type 2 (HSV-2). We found that SVF does not modify the course of primary infection, but markedly improved protection conferred by vaginal vaccination with inactivated HSV-2 against a lethal challenge. This protective effect was shown to be associated to a robust memory immune response mediated by CD4+ and CD8+ T cells in both the lymph nodes draining the vagina and the vaginal mucosa, the site of viral replication. In contrast with the widespread notion that SP acts as an immunosuppressive agent, our results suggest that SVF might improve the female immune response against sexually transmitted pathogens.

Contribution of the T cell receptor to the generation and maintenance of EBV epitopespecific CD8 T cell responses following primary infection

Abstract We have investigated the potential effect of TCRαβ usage on the maintenance and transcriptome of Epstein-Barr virus (EBV)-specific CD8T cells over the course of primary infection. Blood samples were collected over the course of a year from patients presenting with primary EBV infection. Peptide-MHC tetramers and FACS were used to sort CD8 T cells specific for two HLA-A*02-restricted EBV epitopes: BMLF1 (GLCTLVAML; GLC) and BRLF1 (YVLDHLIVV; YVL); single-cell sequencing and transcriptomics were used to evaluate TCRαβ usage with the expression of 47 immune genes. In 4 donors studied, we identified 16 and 4 public GLC- and YVL-specific CDR3αs; and 17 and 2 public GLC- and YVL-specific CDR3βs. The Morisita-Horn index was used to assess the degree of similarity of the TCRαβ repertoire between primary infection and convalescence. GLC-specific cells tended to have a higher similarity index than YVL-specific cells (mean similarity index: 0.55 vs. 0.27), suggesting that the TCRαβ repertoire GLC-specific cells tended to be more stable than that of YVL-specific cells. The similarity index correlated with the frequency of public CDR3α/β clones (Spearman r: 0.83; p = 0.0198), suggesting there may be a survival advantage to public CDR3αβ usage leading to T-cell persistence. 11 and 10 degenerate GLC- and YVL-specific CDR3αs; and 15 and 12 degenerate GLC- and YVL-specific CDR3βs were identified. In a donor, one of these CDR3αs was paired with up to 9 unique CDR3β. Future analyses will focus on single-cell gene expression to investigate whether there are specific gene patterns associated with public or degenerate TCR and T-cell persistence.

Klebsiella spp. in the pathology of poultry and their role in epidemiology of human foodborne diseases

One of the important problems, increasing successively, in intensive poultry production are bacterial infections, and the major reason of this inconvenient situation is increasing resistance of bacteria to antibiotics. In most cases infections are caused by bacteria belonging to the family Enterobacteriaceae, especially Escherichia coli and Salmonella spp. Additionally, bacteria Klebsiella spp. are isolated from many pathological conditions of poultry. To date these bacteria were isolated from dead embryos, yolk sac infections, pathological conditions associated with ascites, cellulitis, diseases with respiratory symptoms and from skin swabs of poultry carcasses. Klebsiella spp. are considered to be microbes of low pathogenicity, but in the case of birds’ immunosuppression they can intensify the course of primary infections. Moreover, an alarming fact is the very wide antimicrobial resistance of strains of these bacteria, and Klebsiella spp. is the frequent cause of critical infections in humans. The presence of these bacteria in poultry, and therefore the possibility of contamination of poultry carcasses, especially if processed without correct heat treatment, may serve as a source of infections for humans, which has been described in the past in studies with the use of phylogenetic analysis.

IS-052 Genetic Theory Of Infectious Diseases

The hypothesis that inborn errors of immunity underlie infectious diseases is gaining experimental support. However, the apparent modes of inheritance of predisposition or resistance differ considerably between diseases and between studies. A coherent genetic architecture of infectious diseases is lacking. We suggest here that life-threatening infectious diseases in childhood, occurring in the course of primary infection, result mostly from individually rare but collectively diverse single-gene variations of variable clinical penetrance, whereas the genetic component of predisposition to secondary or reactivation infections in adults is more complex. This model is consistent with (i) the high incidence of most infectious diseases in early childhood, followed by a steady decline, (ii) theoretical modelling of the impact of monogenic or polygenic predisposition on the incidence distribution of infectious diseases before reproductive age, (iii) available molecular evidence from both monogenic and complex genetics of infectious diseases in children and adults, (iv) current knowledge of immunity to primary and secondary or latent infections, (v) the state of the art in the clinical genetics of non-infectious paediatric and adult diseases, and (vi) evolutionary data for the genes underlying single-gene and complex disease risk. With the recent advent of new-generation deep resequencing, this model of single-gene variations underlying severe paediatric infectious diseases is experimentally testable.

Do the placental barrier, parasite genotype and Toll-like receptor polymorphisms contribute to the course of primary infection with various Toxoplasma gondii genotypes in pregnant women?

Toxoplasma gondii has a highly clonal genetic structure classified into three major genetic types, I, II, and III, plus additional recombinant and atypical strains. In humans, type I and atypical strains usually associate with severe toxoplasmosis. Type II strains, predominantly identified in European countries and the United States, correlate with a differential course of toxoplasmosis. During pregnancy, the important protective role of the placenta against maternal–fetal T. gondii transmission has been reported. T. gondii preferentially colonizes extravillous trophoblasts as compared to syncytiotrophoblasts. The latter compartment was suggested to act as the real barrier to the fetal dissemination of T. gondii. Alterations in immune response to particular T. gondii strains were observed. Higher transcription levels of IP-10, IL-1β, IL-6, IL-10, IL-12 cytokines, and NF-κB translocation to the nucleus were more often documented for type II strains than type I strains. Since the induction of IL-12 during type II infection was Myd88-dependent, the involvement of Toll-like receptors (TLRs) in the immunity against these strains was suggested. Differential expression of TLRs depends on placental cell types and gestational age. The expression of TLR2 and TLR4 in the first trimester of pregnancy was reported only for villous cytotrophoblasts and extravillous trophoblasts, but not for syncytiotrophoblasts. The involvement of single-nucleotide polymorphisms (SNPs) in the TLR genes in infectious pathogenicity, including toxoplasmic retinochoroiditis, points at a possible involvement of TLR alterations in immunity against T. gondii. We conclude that studies on TLR contributions in the maternal–fetal transmission of particular parasite strains and congenital toxoplasmosis are warranted.

Innate immune responses against Epstein Barr virus infection

EBV persists life-long in >95% of the human adult population. Whereas it is perfectly immune-controlled in most infected individuals, a minority develops EBV-associated diseases, primarily malignancies of B cell and epithelial cell origin. In recent years, it has become apparent that the course of primary infection determines part of the risk to develop EBV-associated diseases. Particularly, the primary symptomatic EBV infection or IM, which is caused by exaggerated T cell responses, resulting in EBV-induced lymphocytosis, predisposes for EBV-associated diseases. The role of innate immunity in the development of IM remains unknown. Therefore, it is important to understand how the innate immune response to this virus differs between symptomatic and asymptomatic primary EBV infection. Furthermore, the efficiency of innate immune compartments might determine the outcome of primary infection and could explain why some individuals are susceptible to IM. We will discuss these aspects in this review with a focus on intrinsic immunity in EBV-infected B cells, as well as innate immune responses by DCs and NK cells, which constitute promising immune compartments for the understanding of early immune control against EBV and potential targets for EBV-specific immunotherapies.

The genetic theory of infectious diseases: a brief history and selected illustrations.

Until the mid-nineteenth century, life expectancy at birth averaged 20 years worldwide, owing mostly to childhood fevers. The germ theory of diseases then gradually overcame the belief that diseases were intrinsic. However, around the turn of the twentieth century, asymptomatic infection was discovered to be much more common than clinical disease. Paradoxically, this observation barely challenged the newly developed notion that infectious diseases were fundamentally extrinsic. Moreover, interindividual variability in the course of infection was typically explained by the emerging immunological (or somatic) theory of infectious diseases, best illustrated by the impact of vaccination. This powerful explanation is, however, best applicable to reactivation and secondary infections, particularly in adults; it can less easily account for interindividual variability in the course of primary infection during childhood. Population and clinical geneticists soon proposed a complementary hypothesis, a germline genetic theory of infectious diseases. Over the past century, this idea has gained some support, particularly among clinicians and geneticists, but has also encountered resistance, particularly among microbiologists and immunologists. We present here the genetic theory of infectious diseases and briefly discuss its history and the challenges encountered during its emergence in the context of the apparently competing but actually complementary microbiological and immunological theories. We also illustrate its recent achievements by highlighting inborn errors of immunity underlying eight life-threatening infectious diseases of children and young adults. Finally, we consider the far-reaching biological and clinical implications of the ongoing human genetic dissection of severe infectious diseases.

Impaired intrinsic immunity to HSV-1 in human iPSC-derived TLR3-deficient CNS cells

In the course of primary infection with herpes simplex virus 1 (HSV-1), children with inborn errors of TLR3 immunity are prone to HSV-1 encephalitis (HSE) 1–3. We tested the hypothesis that the pathogenesis of HSE involves non hematopoietic central nervous system (CNS)-resident cells. We derived induced pluripotent stem cells (iPSCs) from the dermal fibroblasts of TLR3- and UNC-93B-deficient patients and from controls. These iPSCs were differentiated into highly purified populations of neural stem cells (NSCs), neurons, astrocytes and oligodendrocytes. The induction of IFN-β and/or IFN-γ1 in response to poly(I:C) stimulation was dependent on TLR3 and UNC-93B in all cells tested. However, the induction of IFN-β and IFN-γ1 in response to HSV-1 infection was impaired selectively in UNC-93B-deficient neurons and oligodendrocytes. These cells were also much more susceptible to HSV-1 infection than control cells, whereas UNC-93B-deficient NSCs and astrocytes were not. TLR3-deficient neurons were also found to be susceptible to HSV-1 infection. The rescue of UNC-93B- and TLR3-deficient cells with the corresponding wild-type allele demonstrated that the genetic defect was the cause of the poly(I:C) and HSV-1 phenotypes. The viral infection phenotype was further rescued by treatment with exogenous IFN-α/β, but not IFN-γ1.Thus, impaired TLR3- and UNC-93B-dependent IFN-α/β intrinsic immunity to HSV-1 in the CNS, in neurons and oligodendrocytes in particular, may underlie the pathogenesis of HSE in children with TLR3 pathway deficiencies.

I01 Toward a genetic theory of infectious diseases

The hypothesis that inborn errors of immunity underlie infectious diseases is gaining experimental support. However, the apparent modes of inheritance of predisposition or resistance differ considerably between diseases and between studies. A coherent genetic architecture of infectious diseases is lacking. We suggest here that life-threatening infectious diseases in childhood, occurring in the course of primary infection, result mostly from individually rare but collectively diverse single-gene variations of variable clinical penetrance, whereas the genetic component of predisposition to secondary or reactivation infections in adults is more complex. This model is consistent with (i) the high incidence of most infectious diseases in early childhood, followed by a steady decline, (ii) theoretical modeling of the impact of monogenic or polygenic predisposition on the incidence distribution of infectious diseases before reproductive age, (iii) available molecular evidence from both monogenic and complex genetics of infectious diseases in children and adults, (iv) current knowledge of immunity to primary and secondary or latent infections, (v) the state of the art in the clinical genetics of non-infectious pediatric and adult diseases, and (vi) evolutionary data for the genes underlying single-gene and complex disease risk. With the recent advent of new-generation deep resequencing, this model of single-gene variations underlying severe pediatric infectious diseases is experimentally testable.

Life‐threatening infectious diseases of childhood: single‐gene inborn errors of immunity?

The hypothesis that inborn errors of immunity underlie infectious diseases is gaining experimental support. However, the apparent modes of inheritance of predisposition or resistance differ considerably among diseases and among studies. A coherent genetic architecture of infectious diseases is lacking. We suggest here that life-threatening infectious diseases in childhood, occurring in the course of primary infection, result mostly from individually rare but collectively diverse single-gene variations of variable clinical penetrance, whereas the genetic component of predisposition to secondary or reactivation infections in adults is more complex. This model is consistent with (i) the high incidence of most infectious diseases in early childhood, followed by a steady decline; (ii) theoretical modeling of the impact of monogenic or polygenic predisposition on the incidence distribution of infectious diseases before reproductive age; (iii) available molecular evidence from both monogenic and complex genetics of infectious diseases in children and adults; (iv) current knowledge of immunity to primary and secondary or latent infections; (v) the state of the art in the clinical genetics of noninfectious pediatric and adult diseases; and (vi) evolutionary data for the genes underlying single-gene and complex disease risk. With the recent advent of new-generation deep resequencing, this model of single-gene variations underlying severe pediatric infectious diseases is experimentally testable.

Two kindred with x-linked recessive tuberculous mycobacterial disease: towards a genetic theory of infectious diseases

The observation that only a small fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. Although many studies have provided proof-of-principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. It is commonly thought that rare patients with multiple infections display Mendelian primary immunodeficiencies, whereas common infections in otherwise healthy patients reflect polygenic predisposition. However, patients cannot be ascribed to such discrete binary categories (rare v. common, multi-infected v. otherwise healthy), and we have previously documented various Mendelian traits predisposing to a single type of infection. For human genetics to establish a new paradigm, the genetic architecture of infectious diseases should be deciphered. Our laboratory tests the hypothesis that life-threatening diseases of childhood, typically in the course of primary infection, each result from a collection of highly diverse but immuno-logically related single-gene variations; whereas the corresponding infections in adults, typically caused by secondary infection or reactivation of latent infection, reflect a more complex predisposition.The genetictheory of infectiousdiseases hasimportant clinical implications, paving the way to novel treatment, aimed at restoring the patients’ immunity to specific pathogens. The immunological implications are equally important, as studies of experiments of nature define the function of host defence genes in natura, i.e., in the setting of a natural ecosystem governed by natural selection. We will illustrate our endeavors in the field of human genetics of infectious diseases by relating the clinical investigation of patients from two unrelated kindreds with X-linked recessive susceptibility to tuberculous mycobacterial diseases. The observation that only a small fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. Although many studies have provided proof-of-principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. It is commonly thought that rare patients with multiple infections display Mendelian primary immunodeficiencies, whereas common infections in otherwise healthy patients reflect polygenic predisposition. However, patients cannot be ascribed to such discrete binary categories (rare v. common, multi-infected v. otherwise healthy), and we have previously documented various Mendelian traits predisposing to a single type of infection. For human genetics to establish a new paradigm, the genetic architecture of infectious diseases should be deciphered. Our laboratory tests the hypothesis that life-threatening diseases of childhood, typically in the course of primary infection, each result from a collection of highly diverse but immuno-logically related single-gene variations; whereas the corresponding infections in adults, typically caused by secondary infection or reactivation of latent infection, reflect a more complex predisposition.The genetictheory of infectiousdiseases hasimportant clinical implications, paving the way to novel treatment, aimed at restoring the patients’ immunity to specific pathogens. The immunological implications are equally important, as studies of experiments of nature define the function of host defence genes in natura, i.e., in the setting of a natural ecosystem governed by natural selection. We will illustrate our endeavors in the field of human genetics of infectious diseases by relating the clinical investigation of patients from two unrelated kindreds with X-linked recessive susceptibility to tuberculous mycobacterial diseases.

Two kindred with x-linked recessive tuberculous mycobacterial disease: towards a genetic theory of infectious diseases

The observation that only a small fraction of individuals infected by infectious agents develop clinical disease raises fundamental questions about the actual pathogenesis of infectious diseases. Epidemiological and experimental evidence is accumulating to suggest that human genetics plays a major role in this process. Although many studies have provided proof-of-principle that infectious diseases may result from various types of inborn errors of immunity, the genetic determinism of most infectious diseases in most patients remains unclear. It is commonly thought that rare patients with multiple infections display Mendelian primary immunodeficiencies, whereas common infections in otherwise healthy patients reflect polygenic predisposition. However, patients cannot be ascribed to such discrete binary categories (rare v. common, multi-infected v. otherwise healthy), and we have previously documented various Mendelian traits predisposing to a single type of infection. For human genetics to establish a new paradigm, the genetic architecture of infectious diseases should be deciphered. Our laboratory tests the hypothesis that life-threatening diseases of childhood, typically in the course of primary infection, each result from a collection of highly diverse but immunologically related single-gene variations; whereas the corresponding infections in adults, typically caused by secondary infection or reactivation of latent infection, reflect a more complex predisposition. The genetic theory of infectious diseases has important clinical implications, paving the way to novel treatment, aimed at restoring the patients’ immunity to specific pathogens. The immunological implications are equally important, as studies of experiments of nature define the function of host defence genes in natura, i.e., in the setting of a natural ecosystem governed by natural selection. We will illustrate our endeavors in the field of human genetics of infectious diseases by relating the clinical investigation of patients from two unrelated kindreds with X-linked recessive susceptibility to tuberculous mycobacterial diseases.

Varicella-zoster virus T cell tropism and the pathogenesis of skin infection.

Varicella-zoster virus (VZV) is a medically important human alphaherpesvirus that causes varicella and zoster. VZV initiates primary infection by inoculation of the respiratory mucosa. In the course of primary infection, VZV establishes a life-long persistence in sensory ganglia; VZV reactivation from latency may result in zoster in healthy and immunocompromised patients. The VZV genome has at least 70 known or predicted open reading frames (ORFs), but understanding how these gene products function in virulence is difficult because VZV is a highly human-specific pathogen. We have addressed this obstacle by investigating VZV infection of human tissue xenografts in the severe combined immunodeficiency mouse model. In studies relevant to the pathogenesis of primary VZV infection, we have examined VZV infection of human T cell (thymus/liver) and skin xenografts. This work supports a new paradigm for VZV pathogenesis in which VZV T cell tropism provides a mechanism for delivering the virus to skin. We have also shown that VZV-infected T cells transfer VZV to neurons in sensory ganglia. The construction of infectious VZV recombinants that have deletions or targeted mutations of viral genes or their promoters and the evaluation of VZV mutants in T cell and skin xenografts has revealed determinants of VZV virulence that are important for T cell and skin tropism in vivo.

Antigen-induced cytokine production in lymphocytes of Eimeria bovis primary and challenge infected calves

Cellular immune responses against Eimeria bovis are highly specific and a key factor for the development of protection against challenge infections. In this study we investigate the cellular immune responses of E. bovis primary and challenge infected calves stimulated in vitro by E. bovis merozoite I-antigen. Primary infection was accompanied by an increase of IFN-γ and IL-2 gene transcription in whole blood samples, peaking during prepatency (8–12 days p.i.) and declining thereafter, whereas IL-4 gene transcription was induced predominantly in patency. IL-10 mRNA was not influenced by E. bovis infection. Both CD4 + and CD8 + T cells were identified as source of IFN-γ gene transcripts, whilst IL-2 and IL-4 gene transcription was enhanced mainly in CD4 + T cells. Increased levels of IFN-γ transcripts and protein were also found in lymphocytes isolated from ileocaecal lymph node biopsy 8 days p.i., and in cell culture supernatants obtained from antigen-stimulated peripheral blood mononuclear cells (PBMC) at days 8 and 12 p.i., respectively. Challenge infections of calves influenced neither IFN-γ nor IL-2 gene transcription in peripheral blood or in lymph node-derived lymphocytes. In contrast, IL-4 gene transcription was increased in lymphocytes isolated from draining lymph nodes. Besides antigen-specific reactions we also found an infection-triggered induction of the non-specific activation state of PBMC in the course of primary infection as measured by the intracellular IFN-γ and IL-4 content of phorbol-12-myristate-13-acetate/ionomycin-stimulated PBMC. This may represent a new mechanism of immune cells of E. bovis-infected calves contributing to ongoing immune reactions.

Comparative Analysis of Viral Gene Expression Programs during Poxvirus Infection: A Transcriptional Map of the Vaccinia and Monkeypox Genomes

BackgroundPoxviruses engage in a complex and intricate dialogue with host cells as part of their strategy for replication. However, relatively little molecular detail is available with which to understand the mechanisms behind this dialogue.Methodology/Principal FindingsWe designed a specialized microarray that contains probes specific to all predicted ORFs in the Monkeypox Zaire (MPXV) and Vaccinia Western Reserve (VACV) genomes, as well as >18,000 human genes, and used this tool to characterize MPXV and VACV gene expression responses in vitro during the course of primary infection of human monocytes, primary human fibroblasts and HeLa cells. The two viral transcriptomes show distinct features of temporal regulation and species-specific gene expression, and provide an early foundation for understanding global gene expression responses during poxvirus infection.Conclusions/SignificanceThe results provide a temporal map of the transcriptome of each virus during infection, enabling us to compare viral gene expression across species, and classify expression patterns of previously uncharacterized ORFs.

A Predominant Role for Antibody in Acquired Immunity to Chlamydial Genital Tract Reinfection

Acquired immunity to murine Chlamydia trachomatis genital tract reinfection has long been assumed to be solely dependent on cell-mediated immunity. However, in this study, we identify a previously unrecognized protective role for Ab. Immunity develops in Ab-deficient mice following the resolution of primary chlamydial genital infection. Subsequent depletion of CD4+ T cells, but not CD8+ T cells, in those immune Ab-deficient mice before secondary infectious challenge, resulted in an infection that did not resolve. Passive immunization with immune (convalescent) serum conferred a marked level of protective immunity to reinfection, which was characterized by a striking decrease in bacterial shedding, from >100,000 inclusion forming units to fewer than 10 inclusion forming units, and a shortened duration of infection. Furthermore, mAbs to the chlamydial major outer membrane protein and LPS conferred significant levels of immunity to reinfection and reduced chlamydial shedding by >100-fold. Anti-heat shock protein 60 mAb had no protective effect. In contrast to the marked protective efficacy of immune serum on reinfection, the course of primary infection was essentially unaltered by the passive transfer of immune serum. Our results convincingly demonstrate that Abs contribute importantly to immunity to chlamydial genital tract reinfection, and that Ab-mediated protection is highly dependent on CD4+ T cell-mediated adaptive changes that occur in the local genital tract tissues during primary infection. These results impact our understanding of immunity to chlamydial genital infection and may provide important insight into vaccine development.

Acquired homotypic and heterotypic immunity against oculogenital Chlamydia trachomatis serovars following female genital tract infection in mice

BackgroundChlamydia trachomatis is the most common sexually transmitted bacterial pathogen causing female genital tract infection throughout the world. Reinfection with the same serovar, as well as multiple infections with different serovars, occurs in humans. Using a murine model of female C. trachomatis genital tract infection, we determined if homotypic and/or heterotypic protection against reinfection was induced following infection with human oculogenital strains of C. trachomatis belonging to two serovars (D and H) that have been shown to vary significantly in the course of infection in the murine model.MethodsGroups of outbred CF-1 mice were reinfected intravaginally with a strain of either serovar D or H, two months after initial infection with these strains. Cellular immune and serologic status, both quantitative and qualitative, was assessed following initial infection, and the course of infection was monitored by culturing vaginal samples collected every 2–7 days following reinfection.ResultsSerovar D was both more virulent (longer duration of infection) and immunogenic (higher level of circulating and vaginal IgG and higher incidence of IgA in vaginal secretions) in the mouse genital tract. Although both serovars induced cross-reacting antibodies during the course of primary infection, prior infection with serovar H resulted in only a slight reduction in the median duration of infection against homotypic reinfection (p ~ 0.10), while prior infection with serovar D resulted in significant reduction in the median duration of infection against both homotypic (p < 0.01) and heterotypic reinfection (p < 0.01) when compared to primary infection in age and conditions matched controls.ConclusionSerovar D infection resulted in significant homotypic and heterotypic protection against reinfection, while primary infection with serovar H resulted in only slight homotypic protection. In addition to being the first demonstration of acquired heterotypic immunity between human oculogenital serovars, the differences in the level and extent of this immunity could in part explain the stable difference in serovar prevalence among human isolates.