Chlamydial infection and spatial ascension of the female genital tract: a novel hybrid cellular automata and continuum mathematical model

Sexually transmitted chlamydial infection initially establishes in the endocervix in females, but if the infection ascends the genital tract, significant disease, including infertility, can result. Many of the mechanisms associated with chlamydial infection kinetics and disease ascension are unknown. We attempt to elucidate some of these processes by developing a novel mathematical model, using a cellular automata–partial differential equation model. We matched our model outputs to experimental data of chlamydial infection of the guinea-pig cervix and carried out sensitivity analyses to determine the relative influence of model parameters. We found that the rate of recruitment and action of innate immune cells to clear extracellular chlamydial particles and the rate of passive movement of chlamydial particles are the dominant factors in determining the early course of infection, magnitude of the peak chlamydial time course and the time of the peak. The rate of passive movement was found to be the most important factor in determining whether infection would ascend to the upper genital tract. This study highlights the importance of early innate immunity in the control of chlamydial infection and the significance of motility-diffusive properties and the adaptive immune response in the magnitude of infection and in its ascension.     

Initial and innate responses to viral infections--pattern setting in immunity or disease.

Host responses to infectious challenges include initial events elicited directly by agent structures distinct from host determinants, activation of innate immune system components by the products of initial events, and the shaping of downstream adaptive immunity by these initial/innate responses. The picture emerging from viral infections is that viral structures interact with intracellular signaling pathways to induce expression of the type 1 interferons, IFN-alpha/beta. In addition to mediating direct antiviral effects, these cytokines play dominant roles in regulating innate and adaptive immune responses to infection. In particular, IFN-alpha/beta acts to inhibit interleukin-12 (IL-12) expression and IL-12 activation of innate natural killer (NK) cell IFN-alpha production, while inducing NK cell cytotoxicity and proliferation, and promoting adaptive T cell IFN-alpha responses. Although certain viral infections do elicit initial/innate IL-12 and NK-cell-produced IFN-alpha, endogenous IFN-alpha/beta also controls the magnitudes of these responses. Thus, the pathways activated, to dominantly regulate innate and adaptive immune responses during viral infections, are being defined.     

MHC-I Affects Infection Intensity but Not Infection Status with a Frequent Avian Malaria Parasite in Blue Tits

Host resistance against parasites depends on three aspects: the ability to prevent, control and clear infections. In vertebrates the immune system consists of innate and adaptive immunity. Innate immunity is particularly important for preventing infection and eradicating established infections at an early stage while adaptive immunity is slow, but powerful, and essential for controlling infection intensities and eventually clearing infections. Major Histocompatibility Complex (MHC) molecules are central in adaptive immunity, and studies on parasite resistance and MHC in wild animals have found effects on both infection intensity (parasite load) and infection status (infected or not). It seems MHC can affect both the ability to control infection intensities and the ability to clear infections. However, these two aspects have rarely been considered simultaneously, and their relative importance in natural populations is therefore unclear. Here we investigate if MHC class I genotype affects infection intensity and infection status with a frequent avian malaria infection Haemoproteus majoris in a natural population of blue tits Cyanistes caeruleus. We found a significant negative association between a single MHC allele and infection intensity but no association with infection status. Blue tits that carry a specific MHC allele seem able to suppress H. majoris infection intensity, while we have no evidence that this allele also has an effect on clearance of the H. majoris infection, a result that is in contrast with some previous studies of MHC and avian malaria. A likely explanation could be that the clearance rate of avian malaria parasites differs between avian malaria lineages and/or between avian hosts.     

Helicobacter pylori Immunology and Vaccines

Helicobacter pylori infection causes chronic gastritis, peptic ulcer, and gastric cancer. Colonization of H. pylori in the stomach activates Toll-like and Nod-like receptors to induce not only innate immunity but also adaptive Th1 responses against this organism. Adaptive Th1 response is not sufficient to clear this organism and, as a result, the infection persists. Insufficient adaptive immunity can be explained by poor activation of Toll-like receptors, suppressive effects of bacterial factors, and induction of regulatory T-cell responses. Significant progress in the understanding of innate and adaptive immunity against H. pylori was made during the past year. Recent findings in the fields of vaccines for H. pylori are also reviewed.     

What Controls the Acute Viral Infection Following Yellow Fever Vaccination?

Does target cell depletion, innate immunity, or adaptive immunity play the dominant role in controlling primary acute viral infections? Why do some individuals have higher peak virus titers than others? Answering these questions is a basic problem in immunology and can be particularly difficult in humans due to limited data, heterogeneity in responses in different individuals, and limited ability for experimental manipulation. We address these questions for infections following vaccination with the live attenuated yellow fever virus (YFV-17D) by analyzing viral load data from 80 volunteers. Using a mixed effects modeling approach, we find that target cell depletion models do not fit the data as well as innate or adaptive immunity models. Examination of the fits of the innate and adaptive immunity models to the data allows us to select a minimal model that gives improved fits by widely used model selection criteria (AICc and BIC) and explains why it is hard to distinguish between the innate and adaptive immunity models. We then ask why some individuals have over 1000-fold higher virus titers than others and find that most of the variation arises from differences in the initial/maximum growth rate of the virus in different individuals.     

Infection History Determines Susceptibility to Unrelated Diseases

Epidemiological data suggest that previous infections can alter an individual's susceptibility to unrelated diseases. Nevertheless, the underlying mechanisms are not completely understood. Substantial research efforts have expanded the classical concept of immune memory to also include long‐lasting changes in innate immunity and antigen‐independent reactivation of adaptive immunity. Collectively, these processes provide possible explanations on how acute infections might induce long‐term changes that also affect immunity to unrelated diseases. Here, we review lasting changes the immune compartment undergoes upon infection and how infection experience alters the responsiveness of immune cells towards universal signals. This heightened state of alert enhances the ability of the immune system to combat even unrelated infections but may also increase susceptibility to autoimmunity. At the same time, infection‐induced changes in the regulatory compartment may dampen subsequent immune responses and promote pathogen persistence. The concepts presented here outline how infection‐induced changes in the immune system may affect human health.     

Identification of lncRNA‐155 encoded by MIR155HG as a novel regulator of innate immunity against influenza A virus infection

Long noncoding RNAs (lncRNAs) are single‐stranded RNA molecules longer than 200 nt that regulate many cellular processes. MicroRNA 155 host gene (MIR155HG) encodes the microRNA (miR)‐155 that regulates various signalling pathways of innate and adaptive immune responses against viral infections. MIR155HG also encodes a lncRNA that we call lncRNA‐155. Here, we observed that expression of lncRNA‐155 was markedly upregulated during influenza A virus (IAV) infection both in vitro (several cell lines) and in vivo (mouse model). Interestingly, robust expression of lncRNA‐155 was also induced by infections with several other viruses. Disruption of lncRNA‐155 expression in A549 cells diminished the antiviral innate immunity against IAV. Furthermore, knockout of lncRNA‐155 in mice significantly increased IAV replication and virulence in the animals. In contrast, overexpression of lncRNA‐155 in human cells suppressed IAV replication, suggesting that lncRNA‐155 is involved in host antiviral innate immunity induced by IAV infection. Moreover, we found that lncRNA‐155 had a profound effect on expression of protein tyrosine phosphatase 1B (PTP1B) during the infection with IAV. Inhibition of PTP1B by lncRNA‐155 resulted in higher production of interferon‐beta (IFN‐β) and several critical interferon‐stimulated genes (ISGs). Together, these observations reveal that MIR155HG derived lncRNA‐155 can be induced by IAV, which modulates host innate immunity during the virus infection via regulation of PTP1B‐mediated interferon response.     

Chlamydial Lung Infection Induces Transient IL-9 Production Which Is Redundant for Host Defense against Primary Infection

IL-9/Th9 responses are recently found to be important for innate and adaptive immunity particularly in parasitic infections. To date, the study on the role of IL-9 in bacterial infections is limited and the reported data are contradictory. One reported function of IL-9/Th9 is to modulate Th1/Th17 responses. Since our and others’ previous work has shown a critical role of Th1 and Th17 cells in host defense against chlamydial lung infection, we here examined the role of IL-9 responses in Chlamydia muridarum (Cm) lung infection, particularly its effect on Th1 and Th17 responses and outcome infection. Our data showed quick but transient IL-9 production in the lung following infection, peaking at day 3 and back to baseline around day 7. CD4+ T cell was the major source of IL-9 production in the lung infection. Blockade of endogenous IL-9 using neutralizing antibody failed to change Interferon-γ (IFN-γ) and IL-17 production by cultured spleen mononuclear cells isolated from Cm infected mice. Similarly, in vivo neutralization of IL-9 failed to show significant effect on T cell (Th1 and Th17) and antibody responses (IgA, IgG1 and IgG2a). Consistently, the neutralization of IL-9 had no significant effect on disease process, including body weight change, bacterial burden and histopathological score. The data suggest that IL-9 production following chlamydial lung infection is redundant for host defense against the intracellular bacteria.     

Influenza-induced innate immunity: regulators of viral replication, respiratory tract pathology & adaptive immunity

Influenza virus infections usually cause mild to moderately severe respiratory disease, however some infections, like those involving the avian H5N1 virus, can cause massive viral pneumonia, systemic disease and death. The innate immune response of respiratory tract resident cells is the first line of defense and limits virus replication. Enhanced cytokine and chemokine production following infection, however, appears to underlie much of the pathology that develops after infection with highly pathogenic strains. A so-called `cytokine storm' can damage the lung tissue and cause systemic disease, despite the control of viral replication. By summarizing current knowledge of the innate responses mounted to influenza infection, this review highlights the importance of the respiratory tract epithelial cells as regulators of innate and adaptive immunity to influenza virus.     

Cross-talking between autophagy and viral infection in mammalian cells

Autophagy is a cellular process in degradation of long-lived proteins and organelles in the cytosol for maintaining cellular homeostasis, which has been linked to a wide range of human health and disease states, including viral infection. The viral infected cells exhibit a complicated cross-talking between autophagy and virus. It has been shown that autophagy interacts with both adaptive and innate immunity. For adaptive immunity, viral antigens can be processed in autophagosomes by acidic proteases before major histocompatibility complex (MHC) class II presentation. For innate immunity, autophagy may assist in the delivery of viral nucleic acids to endosomal TLRs and also functions as a part of the TLR-or-PKR-downstream responses. Autophagy was also reported to suppress the magnitude of host innate antiviral immunity in certain cases. On the other hand, viruses has evolved many strategies to combat or utilize the host autophagy for their own benefit. In this review we discussed recent advances toward clarifying the cross-talking between autophagy and viral infection in mammalian cells.     

Interleukin-21: a multifunctional regulator of immunity to infections

Interleukin-21 (IL-21) is a cytokine that has broad effects on both innate and adaptive immune responses. The roles of IL-21 in determining immunity to infections are currently being defined, and notably, it has been shown that IL-21 is most critical for sustaining T cell responses during chronic viral infections. This article discusses our current understanding of the immunobiology of IL-21, as well as its known and potential roles in influencing immunity to infections.     

Mycobacteria and innate cells: critical encounter for immunogenicity

Protective immunity against mycobacterial infections such as Mycobacterium tuberculosis is mediated by interactions between specific T cells and activated macrophages.To date,many aspects of mycobacterial immunity have shown that innate cells are the key elements that substantially influence the subsequent adaptive host response.During the early phases of infection,phagocytic cells and innate lymphocyte subsets play a pivotal role.Here we summarize the findings of recent investigations on macrophages,dendritic cells and gammadelta T lymphocytes in the response to mycobacteria.     

Adaptive and innate transforming growth factor beta signaling impact herpes simplex virus 1 latency and reactivation

Innate and adaptive immunity play important protective roles by combating herpes simplex virus 1 (HSV-1) infection. Transforming growth factor β (TGF-β) is a key negative cytokine regulator of both innate and adaptive immune responses. Yet, it is unknown whether TGF-β signaling in either immune compartment impacts HSV-1 replication and latency. We undertook genetic approaches to address these issues by infecting two different dominant negative TGF-β receptor type II transgenic mouse lines. These mice have specific TGF-β signaling blockades in either T cells or innate cells. Mice were ocularly infected with HSV-1 to evaluate the effects of restricted innate or adaptive TGF-β signaling during acute and latent infections. Limiting innate cell but not T cell TGF-β signaling reduced virus replication in the eyes of infected mice. On the other hand, blocking TGF-β signaling in either innate cells or T cells resulted in decreased latency in the trigeminal ganglia of infected mice. Furthermore, inhibiting TGF-β signaling in T cells reduced cell lysis and leukocyte infiltration in corneas and trigeminal ganglia during primary HSV-1 infection of mice. These findings strongly suggest that TGF-β signaling, which generally functions to dampen immune responses, results in increased HSV-1 latency.     

Toll-like receptor adaptor molecules enhance DNA-raised adaptive immune responses against influenza and tumors through activation of innate immunity

Toll-like receptors (TLRs) recognize microbial components and trigger the signaling cascade that activates the innate and adaptive immunity. TLR adaptor molecules play a central role in this cascade; thus, we hypothesized that overexpression of TLR adaptor molecules could mimic infection without any microbial components. Dual-promoter plasmids that carry an antigen and a TLR adaptor molecule such as the Toll-interleukin-1 receptor domain-containing adaptor-inducing beta interferon (TRIF) or myeloid differentiation factor 88 (MyD88) were constructed and administered to mice to determine if these molecules can act as an adjuvant. A DNA vaccine incorporated with the MyD88 genetic adjuvant enhanced antigen-specific humoral immune responses, whereas that with the TRIF genetic adjuvant enhanced cellular immune responses. Incorporating the TRIF genetic adjuvant in a DNA vaccine targeting the influenza HA antigen or the tumor-associated antigen E7 conferred superior protection. These results indicate that TLR adaptor molecules can bridge innate and adaptive immunity and potentiate the effects of DNA vaccines against virus infection and tumors.     

Interleukin-13 promotes susceptibility to chlamydial infection of the respiratory and genital tracts

Chlamydiae are intracellular bacteria that commonly cause infections of the respiratory and genital tracts, which are major clinical problems. Infections are also linked to the aetiology of diseases such as asthma, emphysema and heart disease. The clinical management of infection is problematic and antibiotic resistance is emerging. Increased understanding of immune processes that are involved in both clearance and immunopathology of chlamydial infection is critical for the development of improved treatment strategies. Here, we show that IL-13 was produced in the lungs of mice rapidly after Chlamydia muridarum (Cmu) infection and promoted susceptibility to infection. Wild-type (WT) mice had increased disease severity, bacterial load and associated inflammation compared to IL-13 deficient (-/-) mice as early as 3 days post infection (p.i.). Intratracheal instillation of IL-13 enhanced bacterial load in IL-13-/- mice. There were no differences in early IFN-g and IL-10 expression between WT and IL-13-/- mice and depletion of CD4+ T cells did not affect infection in IL-13-/- mice. Collectively, these data demonstrate a lack of CD4+ T cell involvement and a novel role for IL-13 in innate responses to infection. We also showed that IL-13 deficiency increased macrophage uptake of Cmu in vitro and in vivo. Moreover, the depletion of IL-13 during infection of lung epithelial cells in vitro decreased the percentage of infected cells and reduced bacterial growth. Our results suggest that enhanced IL-13 responses in the airways, such as that found in asthmatics, may promote susceptibility to chlamydial lung infection. Importantly the role of IL-13 in regulating infection was not limited to the lung as we showed that IL-13 also promoted susceptibility to Cmu genital tract infection. Collectively our findings demonstrate that innate IL-13 release promotes infection that results in enhanced inflammation and have broad implications for the treatment of chlamydial infections and IL-13-associated diseases.     

Innate and adaptive determinants of host susceptibility to medically important fungi

The host response is the outcome of an interplay between innate immunity, adaptive immunity (Th1, Th2, T regulatory cells, B cells and antibodies) and fungal virulence factors. Dendritic cells are the gatekeepers between innate and adaptive immunity and have been the intense focus of recent studies on innate immunity to fungi because of their ability to distinguish between different forms of a fungal species, to drive Th1 versus Th2 versus T regulatory responses, and potentially be modulated by fungal products. New mechanisms have been described by which anti-fungal antibodies can modulate infection and augment T cell immunity. Th1 responses are central to limiting infection with many fungi; thus, a great deal of attention has been focused recently on the antigen(s) that trigger such a response.     

Complement C3 opsonization of Chlamydia trachomatis facilitates uptake in human monocytes

Chlamydia trachomatis is an obligate intracellular bacterium that causes severe infections, which can lead to infertility and ectopic pregnancy. Although both innate and adaptive immune responses are elicited during chlamydial infection the bacterium succeeds to evade host defense mechanisms establishing chronic infections. Thus, studying the host–pathogen interaction during chlamydial infection is of importance to understand how C. trachomatis can cause chronic infections. Both the complement system and monocytes play essential roles in anti-bacterial defense, and, therefore, we investigated the interaction between the complement system and the human pathogens C. trachomatis D and L2.Complement competent serum facilitated rapid uptake of both chlamydial serovars into monocytes. Using immunoelectron microscopy, we showed that products of complement C3 were loosely deposited on the bacterial surface in complement competent serum and further characterization demonstrated that the deposited C3 product was the opsonin iC3b. Using C3-depleted serum we confirmed that complement C3 facilitates rapid uptake of chlamydiae into monocytes in complement competent serum. Complement facilitated uptake did not influence intracellular survival of C. trachomatis or C. trachomatis-induced cytokine secretion. Hence, C. trachomatis D and L2 activate the complement system leading to chlamydial opsonization by iC3b and subsequent phagocytosis, activation and bacterial elimination by human monocytes.     

Persistent chlamydiae: from cell culture to a paradigm for chlamydial pathogenesis.

Chlamydiae are medically important bacteria responsible for a wide range of human infections and diseases. Repeated episodes of infection promote chronic inflammation associated with detrimental immune system-mediated pathologic changes. However, the true nature of chlamydial pathogenesis may encompass repeated infection superimposed upon persistent infection, which would allow for heightened immune reactivity. During the course of chlamydial infection, numerous host elaborated factors with inhibitory or modifying effects may cause alterations in the chlamydia-host cell relationship such that the organism is maintained in a nonproductive stage of growth. Abnormal or persistent chlamydiae have been recognized under a variety of cell culture systems. The numerous factors associated with altered growth suggest an innate flexibility in the developmental cycle of chlamydiae. This review evaluates in vitro studies of chlamydial persistence and correlates these model systems to features of natural chlamydial disease.