THE IMMUNOLOGICAL BASIS OF ACQUIRED CELLULAR RESISTANCE

The resistance developed by mice during infection with Listeria monocytogenes, Brucella abortus, or Mycobacterium tuberculosis is not specifically directed against the infecting organism. The processes involved in the induction of acquired resistance, however, are highly specific and seem to depend upon two factors: a state of immunological reactivity of the host and the presence of the specific microbial antigens to which the host has become reactive. When these two coexist in the tissues the host is found to be non-specifically resistant. It is suggested that resistance, which was shown to depend upon an altered state of host macrophages, may be due to the interaction of antigen and a specific antibody adsorbed to the surface of host macrophages; and that the antibody involved in the reaction is perhaps identical with the antibody which confers the state of delayed-type hypersensitivity. The results are discussed in relation to the question of latent infection and infection immunity.     

Spontaneous elaboration of transforming growth factor beta suppresses host defense against bacterial infection in autoimmune MRL/lpr mice

Infection with gram-negative and gram-positive bacteria remains a leading cause of death in patients with systemic lupus erythematosis (SLE), even in the absence of immunosuppressive therapy. To elucidate the mechanisms that underly the increased risk of infection observed in patients with systemic autoimmunity, we have investigated host defense against bacterial infection in a murine model of autoimmunity, the MRL/Mp-lpr/lpr (MRL/lpr) mouse. Our previous study implicated transforming growth factor beta (TGF-beta) in a novel acquired defect in neutrophil function in MRL/lpr but not congenic MRL/Mp-+/+ (MRL/n) mice (Gresham, H.D., C.J. Ray, and F.K. O'Sullivan. 1991. J. Immunol. 146:3911). We hypothesized from these observations that MRL/lpr mice would have defects in host defense against bacterial infection and that they would have constitutively higher local and systemic levels of active TGF-beta which would be responsible, at least in part, for the defect in host defense. We show in this paper that spontaneous elaboration of active TGF-beta adversely affects host defense against both gram-negative and gram-positive bacterial infection in MRL/lpr mice. Our data indicate that MRL/lpr mice, as compared with congenic MRL/n mice, exhibit decreased survival in response to bacterial infection, that polymorphonuclear leukocytes (PMN) from MRl/lpr mice fail to migrate to the site of infection during the initial stages of infection, that MRL/lpr mice have a significantly increased bacterial burden at the site of infection and at other tissue sites, and that this increased bacterial growth occurs at a time (> 20 h after infection) when PMN influx is greatly enhanced in MRL/lpr mice. Most intriguingly, the alteration in PMN extravasation during the initial stages of infection and failure to restrict bacterial growth in vivo could be duplicated in MRL/n mice with a parenteral injection of active TGF-beta 1 at the time of bacterial challenge. Moreover, these alterations in host defense, including survival in response to lethal infection, could be ameliorated in MRL/lpr mice by the parenteral administration of a monoclonal antibody that neutralizes the activity of TGF-beta. These data indicate that elaboration of TGF-beta as a result of autoimmune phenomenon suppresses host defense against bacterial infection and that such a mechanism could be responsible for the increased risk of bacterial infection observed in patients with autoimmune diseases.     

The host response to cancer virotherapy

Clinical trials of oncolytic viruses (OVs) for cancers have revealed that these agents are well tolerated. However, clear-cut evidence of efficacy has been elusive. Although investigators are attempting to generate more efficacious OVs, a fundamental issue continues to limit the efficacy of cancer virotherapy - the response of the host to the ongoing viral infection. This response occurs at the level of intracellular tumor defenses to the viral infection, extracellular stromal reactions to the propagating virus, and, importantly, active host defenses consisting of innate immune as well as inflammatory angiogenic responses. The combination of these host responses severely limits and curtails tumor cell infection and viral replication, thus limiting anticancer efficacy. We believe that such host responses have to be circumvented, at least temporarily or partially, or both, in order to fulfill the promising anticancer effects of these agents.     

Immunomodulation and sepsis: impact of the pathogen

Infection begins when microorganisms overcome host barriers and multiply within host tissues. To contain the infection, the host mounts an inflammatory response that mobilizes defense systems and kills the invading microorganisms. A focal inflammatory response is usually sufficient to eradicate the organisms. However, when it fails to contain the infection, the organisms, their toxins, and numerous host mediators are released into the bloodstream, producing a systemic inflammatory response and organ failure. Microorganisms have coevolved with their hosts, thereby acquiring means of overcoming host defense mechanisms or even taking advantage of innate host responses. Many pathogens avoid recognition by the host or dampen host immune responses via sophisticated pathogen-host interactions. Some pathogens benefit from the inflammatory response. According to current hypotheses regarding the pathogenesis of sepsis, the host generates both an innate immune response identical for all pathogens and an adaptive pathogen-specific response. Determining whether the innate response benefits the pathogen or the host is essential for understanding host-pathogen interactions. In this review, we discuss how pathogens interfere with innate and adaptive immune responses to escape eradication by the host.     

Endotoxin and cytokines induce expression of leptin, the ob gene product, in hamsters.

The expression of leptin, the ob gene product, is increased in adipose tissue in response to feeding and energy repletion, while leptin decreases food intake. Because adipose tissue gene expression is regulated by cytokines induced during infection and because infection is associated with anorexia, we tested whether induction of leptin might occur during the host response to infection. Administration of endotoxin (LPS), a model for gram negative infections, induces profound anorexia and weight loss in hamsters. In fasted adipose tissue to levels similar to fed control animals. There is a strong inverse correlation between mRNA levels of leptin and subsequent food intake. TNF and IL-1, mediators of the host response to LPS, also induced anorexia and increased levels of leptin in mRNA in adipose tissue. As assessed by immuknoprecipitation and Western blotting, circulating leptin protein is regulated by LPS and cytokines in parallel to regulation of adipose tissue leptin mRNA. Induction of leptin during the host response to infection may contribute to the anorexia of infection.     

H. pylori infection: bacterial virulence factors and cytokine gene polymorphisms as determinants of infection outcome

The gram negative bacterium H. pylori infects the human stomach worldwide, invariably causing mucosal inflammation. In the majority of cases, H. pylori-associated gastritis remains the only clinical manifestation of the infection, which might cause, otherwise, peptic ulcer, gastric adenocarcinoma. or MALToma. The balance between the bacterial virulence machinery and the host response to the infection determines the different clinical outcomes. The main bacterial virulence factors comprise adhesins (BabA, SabA), the vacuolating cytotoxin VacA, and the products of cag pathogenicity island. The pattern of cytokine production in response to the infection is one of the main host determinants involved in limiting the infection outcome to gastritis or in favoring peptic ulcer or cancer onset. The polymorphisms of some cytokine genes (IL-1beta IL-1RN, TNF-alpha, IFN-gamma) have been correlated with H. pylori-associated gastric adenocarcinoma or peptic ulcer, possibly because they influence the amount of cytokine production in response to H. pylori infection. This review focuses on the role of H. pylori virulence genes and on host cytokines' genes polymorphisms in determining clinical outcome to H. pylori infection.     

Genome Expression Profiling-Based Identification and Administration Efficacy of Host-Directed Antimicrobial Drugs against Respiratory Infection by Nontypeable Haemophilus influenzae

Therapies that are safe, effective, and not vulnerable to developing resistance are highly desirable to counteract bacterial infections. Host-directed therapeutics is an antimicrobial approach alternative to conventional antibiotics based on perturbing host pathways subverted by pathogens during their life cycle by using host-directed drugs. In this study, we identified and evaluated the efficacy of a panel of host-directed drugs against respiratory infection by nontypeable Haemophilus influenzae (NTHi). NTHi is an opportunistic pathogen that is an important cause of exacerbation of chronic obstructive pulmonary disease (COPD). We screened for host genes differentially expressed upon infection by the clinical isolate NTHi375 by analyzing cell whole-genome expression profiling and identified a repertoire of host target candidates that were pharmacologically modulated. Based on the proposed relationship between NTHi intracellular location and persistence, we hypothesized that drugs perturbing host pathways used by NTHi to enter epithelial cells could have antimicrobial potential against NTHi infection. Interfering drugs were tested for their effects on bacterial and cellular viability, on NTHi-epithelial cell interplay, and on mouse pulmonary infection. Glucocorticoids and statins lacked in vitro and/or in vivo efficacy. Conversely, the sirtuin-1 activator resveratrol showed a bactericidal effect against NTHi, and the PDE4 inhibitor rolipram showed therapeutic efficacy by lowering NTHi375 counts intracellularly and in the lungs of infected mice. PDE4 inhibition is currently prescribed in COPD, and resveratrol is an attractive geroprotector for COPD treatment. Together, these results expand our knowledge of NTHi-triggered host subversion and frame the antimicrobial potential of rolipram and resveratrol against NTHi respiratory infection.     

Host defence against disseminated Candida albicans infection and implications for antifungal immunotherapy

The different manifestations of Candida albicans infection are dictated by an underlying defect in the immune response of the host. Protective immunity to disseminated candidiasis, the manifestation of C. albicans infection discussed in this review, has traditionally been ascribed to innate immunity with emphasis on the role of granulocytes. Lately, however, immunological studies have learned that host defence against disseminated candidiasis is based on a complex interplay between innate and cell-mediated immunity. Despite the availability of new antifungal agents, mortality associated with disseminated C. albicans infection remains high. Immunotherapy that augments host defence is an important strategic option in the battle against disseminated candidiasis. Here, the authors review the chronological events in the pathogenesis of disseminated candidiasis that aid in predicting the impact of existing immunotherapy and the development of future immunomodulating strategies.     

Highly selective escape from KSHV-mediated host mRNA shutoff and its implications for viral pathogenesis

During Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) lytic infection, many virus-encoded signaling molecules (e.g., viral G protein-coupled receptor [vGPCR]) are produced that can induce host gene expression in transiently transfected cells, and roles for such induced host genes have been posited in KS pathogenesis. However, we have recently found that host gene expression is strongly inhibited by 10-12 h after lytic reactivation of KSHV, raising the question of whether and to what extent de novo host gene expression induced by viral signaling molecules can proceed during the lytic cycle. Here, we show by microarray analysis that expression of most vGPCR target genes is drastically curtailed by this host shutoff. However, rare cellular genes can escape the host shutoff and are potently up-regulated during lytic KSHV growth. Prominent among these is human interleukin-6, whose striking induction may contribute to the overexpression of this cytokine in several disease states linked to KSHV infection.     

Cytokines and chemokines induced by influenza virus infection

Many kinds of cytokines and chemokines are produced in response to influenza virus infection through the course of cytokine cascade. Even a single cytokine exhibits various biological activities and different types of cells produce the same identical cytokine. In general, cytokines act to maintain the homeostasis of host condition. In influenza virus infection, it works as protective for the host against virus infection at its early stage, but often as pathogenic in its later stage. Cytokines play a pivotal role in establishment of virus specific immunity. However, over expression of cytokines causes irreversible severe damages to the host, including shock, disseminated intravascular coagulation, adult respiratory distress syndrome and multiple organ failure, a typical form of which is influenza encephalopathy. Pathogenicity of influenza virus might be determined by means of its potential capability to induce proinflammatory cytokines.     

THE MITOTIC POTENTIAL OF FIXED PHAGOCYTES IN THE LIVER AS REVEALED DURING THE DEVELOPMENT OF CELLULAR IMMUNITY

Fixed macrophages in the liver of the mouse undergo mitosis in large numbers during an infection with Listeria monocytogenes. The macrophage mitotic response always precedes the expression of efficient host immunity to infection. It is suggested that macrophage proliferation is an important event in the development of host immunity to L. monocytogenes.     

Chlamydia inhibit host cell apoptosis by degradation of proapoptotic BH3-only proteins

Chlamydia are obligate intracellular bacteria that replicate in a vacuole inside a host cell. Chlamydial infection has been shown to protect the host cell against apoptotic stimuli. This is likely important for the ability of Chlamydia to reproduce in human cells. Here we show that resistance to apoptosis is conveyed by the destruction of the proapoptotic BH3-only proteins Bim/Bod, Puma, and Bad during infection. Apoptotic stimuli were blocked upstream of the mitochondrial activation of Bax/Bak. During infection with both species, Chlamydia trachomatis and Chlamydia pneumoniae, Bim protein gradually disappeared without noticeable changes in Bim mRNA. The disappearance was blocked by inhibitors of the proteasome. Infected cells retained sensitivity to Bim expressed by transfection, indicating functional relevance of the Bim disappearance. Fusion to Bim targeted the green fluorescent protein for destruction during infection. Analysis of truncation mutants showed that a short region of Bim containing the BH3 domain was sufficient for destruction during chlamydial infection. Like Bim, Puma and Bad proteins disappeared during infection. These results reveal a novel way by which microbes can interfere with the host cell's apoptotic machinery, and provide a molecular explanation of the cellular resistance to apoptosis during infection with Chlamydia.     

Immunomodulation et sepsis – Impact de l’agent pathogène

Infection begins when micro-organisms overcome host barriers and multiply within host tissue. To contain infection, the host stages an inflammatory reaction to mobilize defence systems and kill the invading micro-organisms. In most cases, the activated defence mechanisms lead to eradication of infection throught a localized inflammatory reaction. However, when the infectious stimulus cannot be contained within tissues, infectious agents, their toxins, and host-derived mediators are released into the circulation leading to a systemic inflammatory response syndrome and remote organ dysfunction. It appears that microbial organisms have coevolved with their hosts to overcome protective host barriers and in selected cases, actually take advantage of innate host responses. Many microbial pathogens avoid host responses recognition or dampen the subsequent immune activation through sophisticated interactions with host responses, but some pathogens benefit from the stimulation if inflammatory reactions. The pathogenesis of sepsis assumes that host are capable to generate unique common responses to any pathogen but also exhibit different pathogen-specific immune responses. Determining whether the unique responses are advantageous to the pathogen or to the host is essential for understanding host-pathogen interactions. In this review, we will discuss how pathogens interfere with innate and adaptative immune responses in order to evade the immune response.     

Peripheral blood leukocyte count as an index of defense status in the leukopenic host

These experimental studies have investigated the reliability of the peripheral blood leukocyte count to predict whether the leukopenic host can contain or eliminate infection. Additionally, we have investigated the possibility that determination of leukocyte recruitment, supplementary to peripheral blood leukocyte counts, might allow individuals with neutropenia at risk from serious infection to be distinguished with greater certainty. Varying doses of radiation, cyclophosphamide, and methylprednisolone were used to induce distinct levels of leukopenia in rats. Leukocyte recruitment was measured by quantifying the response of neutropenic animals to evocative, subcutaneous stimuli, and the results of this assay were then compared with circulating leukocyte counts in the same individuals. Six models of experimentally induced infection were used to compare circulating and recruitable leukocytes as indicators of the susceptibility of the leukopenic host to infection. Response curves relating leukocyte numbers to host resistance were similar when circulating or recruitable leukocytes were used as an index of defense capability. These findings support the use of peripheral blood leukocyte numbers as an index of resistance to infection in individuals with leukopenia and suggest that functional analyses such as leukocyte recruitment are unlikely to provide additional information.     

Serotonin and melatonin, neurohormones for homeostasis, as novel inhibitors of infections by the intracellular parasite chlamydia

OBJECTIVES: Chlamydiae are obligate intracellular bacteria, causing a variety of diseases, i.e. pneumonia, sexually transmitted disease, conjunctivitis and zoonosis. Tryptophan depletion by interferon-gamma (IFN-gamma) is the most important host defence system against chlamydial infection. Thus chlamydial tryptophan metabolism is thought to play key roles for IFN-gamma resistance, persistent infection and host/tissue tropisms. We tested tryptophan derivatives for activity against chlamydia-infected cells. METHODS: Rates of chlamydial infection and sizes of the inclusions were evaluated by in vitro infection using three Chlamydiaceae species, Chlamydia trachomatis, Chlamydophila pneumoniae and Chlamydophila felis, which show significant divergence of tryptophan synthesis genes and different susceptibilities to IFN-gamma. RESULTS: Melatonin and serotonin, which are recognized as neural hormones for maintenance of organism homeostasis, reduced chlamydial infection but not other bacterial growth tested here. Unlike IFN-gamma, melatonin limited infection of all three chlamydiae and the effects were not recovered by tryptophan supplementation. Melatonin treatment only of host cells could diminish infection and the infection reduction was neutralized by a pertussis toxin, an inhibitor of G proteins. Ligands of melatonin and serotonin receptors also hampered infection. CONCLUSIONS: Inhibition mechanisms of chlamydial infection by melatonin and serotonin appear to be different from those of IFN-gamma and involve specific G-protein-coupled receptors. Melatonin is deemed to inhibit early progression of the chlamydial development cycle, such as establishment of intracellular infection and/or conversion from elementary body to reticulate body. Utilization of melatonin, serotonin or their derivatives may be advantageous for harmless prevention of chlamydial infection.     

Genetic susceptibility and resistance to influenza infection and disease in humans and mice

Although genetic risk factors for influenza infection have not yet been defined in people, differences in genetic background and related variation in the response to infection, as well as viral virulence, are all likely to influence both the likelihood of infection and disease severity. However, apart from characterization of viral binding sites in avian and mammalian hosts, relatively little investigation has focused on host genetic determinants of susceptibility or resistance to infection, or the severity of the associated disease in humans or other species. Similarly, the role of genetic background in the generation of an efficacious immune response to either infection or vaccination has not been extensively evaluated. However, genetic influences on susceptibility and resistance to numerous infectious agents and on the resultant host inflammatory and immune responses are well established in both humans and other animals. Mouse-adapted strains of human influenza viruses and the use of inbred strains of laboratory mice have supported extensive characterization of the pathogenesis and immunology of influenza virus infections. Like individual humans, inbred strains of mice vary in their reactions to influenza infection, particularly with regard to the inflammatory response and disease severity, supporting the potential use of these mice as a valuable surrogate for human genetic variation. Relying heavily on what we have learned from mice, this overview summarizes existing animal, human and epidemiologic data suggestive of host genetic influences on influenza infection.     

Role of intestinal epithelial cells in the host secretory response to infection by invasive bacteria. Bacterial entry induces epithelial prostaglandin h synthase-2 expression and prostaglandin E2 and F2alpha production.

Increased intestinal fluid secretion is a protective host response after enteric infection with invasive bacteria that is initiated within hours after infection, and is mediated by prostaglandin H synthase (PGHS) products in animal models of infection. Intestinal epithelial cells are the first host cells to become infected with invasive bacteria, which enter and pass through these cells to initiate mucosal, and ultimately systemic, infection. The present studies characterized the role of intestinal epithelial cells in the host secretory response after infection with invasive bacteria. Infection of cultured human intestinal epithelial cell lines with invasive bacteria, but not noninvasive bacteria, is shown to induce the expression of one of the rate-limiting enzymes for prostaglandin formation, PGHS-2, and the production of PGE2 and PGF2alpha. Furthermore, increased PGHS-2 expression was observed in intestinal epithelial cells in vivo after infection with invasive bacteria, using a human intestinal xenograft model in SCID mice. In support of the physiologic importance of epithelial PGHS-2 expression, supernatants from bacteria-infected intestinal epithelial cells were shown to increase chloride secretion in an in vitro model using polarized epithelial cells, and this activity was accounted for by PGE2. These studies define a novel autocrine/paracrine function of mediators produced by intestinal epithelial cells in the rapid induction of increased fluid secretion in response to intestinal infection with invasive bacteria.     

Antiviral agents for non-human immunodeficiency virus infections

Several new agents for treating viral infections have been developed in recent years. All available agents are virustatic, inhibiting specific steps in the process of viral replication. No agent is active against nonreplicating or latent viruses. Acyclovir is useful in the treatment of genital herpes, herpes simplex encephalitis, mucocutaneous herpetic infection, varicella infection in the immunosuppressed host, and herpes zoster infection in the normal and the immunosuppressed host. It can also be used for prevention of herpesvirus infection in immunocompromised patients. Ganciclovir is indicated for the treatment of cytomegalovirus retinitis in patients with the acquired immunodeficiency syndrome and is effective in the treatment and prevention of cytomegalovirus infection in other immunocompromised patients. Famciclovir and valacyclovir are effective in the management of herpes simplex and varicella-zoster infection. Amantadine and rimantadine are useful therapeutically and prophylactically in the management of influenza A virus infection. Chronic hepatitis B infection can respond to lamivudine therapy, and the optimal treatment of hepatitis C is the combination of interferon alfa and ribavirin. Despite pronounced toxic effects, foscarnet and cidofovir are effective antiviral agents in specific settings.     

Bench-to-bedside review: Bacterial pneumonia with influenza - pathogenesis and clinical implications

Seasonal and pandemic influenza are frequently complicated by bacterial infections, causing additional hospitalization and mortality. Secondary bacterial respiratory infection can be subdivided into combined viral/bacterial pneumonia and post-influenza pneumonia, which differ in their pathogenesis. During combined viral/bacterial infection, the virus, the bacterium and the host interact with each other. Post-influenza pneumonia may, at least in part, be due to resolution of inflammation caused by the primary viral infection. These mechanisms restore tissue homeostasis but greatly impair the host response against unrelated bacterial pathogens. In this review we summarize the underlying mechanisms leading to combined viral/bacterial infection or post-influenza pneumonia and highlight important considerations for effective treatment of bacterial pneumonia during and shortly after influenza.     

Molecular adaptation of Borrelia burgdorferi in the murine host

An analysis of expression of 137 lipoprotein genes on the course of murine infection revealed a two-step molecular adaptation by Borrelia burgdorferi, the Lyme disease spirochete. For the first step, regardless whether the initial inocula of B. burgdorferi expressed either all (cultured spirochetes) or less than 40 (host-adapted spirochetes) of the 137 lipoprotein genes, the spirochetes were modulated to transcribe 116 of the genes within 10 d after being introduced to the murine host. This step of adaptation was induced by the microenvironment of the host tissue. During the second step, which was forced by host immune selection pressure and occurred between 17 and 30 d after infection, B. burgdorferi down-regulated most of the lipoprotein genes and expressed less than 40 of the 137 genes. This novel adaptation mechanism could be a critical step for B. burgdorferi to proceed to chronic infection, as the pathogen would be cleared at the early stage of infection if the spirochetes failed to undergo this process.