Immune response to poxvirus infections in various animals

The study of infections of vertebrate animals by poxviruses has remained a dynamic area of research for the last century. The host range of poxviruses vary from extremely narrow to exceedingly broad, and they have been shown to enter their host by either the respiratory route or through the skin. The severity of infection varies dramatically from one species to another, causing anywhere from a local, self-limiting infection, to a devastating systemic disease, such as smallpox. Although the immune response to poxvirus infections are very similar to that seen in other viral infections, the poxviruses, unlike most other viruses (with the exception of Herpes viruses), are able to defend themselves. They have been shown to carry a repertoire of proteins involved in immune evasion and immune modulation. Poxviruses encode proteins involved in blocking many of the strategies employed by the host to combat viral infections; they encode for proteins that block activity of many chemokines, cytokines, serine proteases, and even complement. Traditionally, different animal models have been used to study the pathogenesis of poxvirus infections, and the characterization of virulence genes using mutant poxviruses. Additionally, new animal models are being developed to study the possible therapeutic uses many of these poxvirus immune modulating proteins might have. This review discusses the host immune response against poxvirus infections in various animals, the viral counter response to the host, and the animal models used to study poxvirus infection and immune modulating proteins.     

Immune Response to Poxvirus Infections in Various Animals

The study of infections of vertebrate animals by poxviruses has remained a dynamic area of research for the last century. The host range of poxviruses vary from extremely narrow to exceedingly broad, and they have been shown to enter their host by either the respiratory route or through the skin. The severity of infection varies dramatically from one species to another, causing anywhere from a local, self-limiting infection, to a devastating systemic disease, such as smallpox. Although the immune response to poxvirus infections are very similar to that seen in other viral infections, the poxviruses, unlike most other viruses (with the exception of Herpes viruses), are able to defend themselves. They have been shown to carry a repertoire of proteins involved in immune evasion and immune modulation. Poxviruses encode proteins involved in blocking many of the strategies employed by the host to combat viral infections; they encode for proteins that block activity of many chemokines, cytokines, serine proteases, and even complement. Traditionally, different animal models have been used to study the pathogenesis of poxvirus infections, and the characterization of virulence genes using mutant poxviruses. Additionally, new animal models are being developed to study the possible therapeutic uses many of these poxvirus immune modulating proteins might have. This review discusses the host immune response against poxvirus infections in various animals, the viral counter response to the host, and the animal models used to study poxvirus infection and immune modulating proteins.     

Intestinal nematode infection ameliorates experimental colitis in mice

Epidemiological studies suggest that inflammatory bowel disease (IBD) is common in developed countries and rare in countries where intestinal nematode infections are common. T cells are critical in many immune responses, including those associated with IBD and nematode infection. Among the distinct T helper (Th) cell subsets, Th1-type immune response is predominantly associated with Crohn's disease, while many nematode infections generate a strong Th2 response. The reciprocal cross regulation between Th1 and Th2 cells suggests that generation of a Th2 response by nematodes could prevent or reduce the effects of Th1-mediated diseases. In the present study, we investigated the effect of polarizing the immune response toward the Th2 type, using intestinal nematode infection, on subsequent experimental colitis. Mice were infected with the intestinal nematode Trichinella spiralis and allowed to recover before colitis was induced with dinitrobenzene sulfonic acid. The mice were sacrificed postcolitis to assess colonic damage macroscopically, histologically, and by myeloperoxidase (MPO) activity and Th cytokines. Prior nematode infection reduced the severity of colitis both macroscopically and histologically together with a decreased mortality and was correlated with a down-regulation of MPO activity, Th1-type cytokine expression in colonic tissue, and emergence of a Th2-type immune response. These results indicate a protective role of nematode infection in Th1 cell-driven inflammation and prompt consideration of a novel therapeutic strategy in IBD based on immunological distraction.     

The role of viral infections in the development of autoimmune diseases

Abstract

The exact aetiology of most autoimmune diseases remains unknown, nonetheless, several factors contributing to the induction or exacerbation of autoimmune reactions have been suggested. These include the genetic profile and lifestyle of the affected individual in addition to environmental triggers such as bacterial, parasitic, fungal and viral infections. Infections caused by viruses usually trigger a potent immune response that is necessary for the containment of the infection; however, in some cases, a failure in the regulation of this immune response may lead to harmful immune reactions directed against the host’s antigens. The autoimmune attack can be carried out by different arms and components of the immune system and through different possible mechanisms including molecular mimicry, bystander activation, and epitope spreading among others. In this review, we examine the data available for the involvement of viral infections in triggering or exacerbating autoimmune diseases in addition to discussing the mechanisms by which these viral infections and the immune pathways they trigger possibly contribute to the development of autoimmunity.     

Genes important in the parasitic life of the nematode Strongyloides ratti

Parasitic nematodes are important pathogens of humans and other animals. The genus Strongyloides has both a parasitic and a free-living adult generation. S. ratti infections of its rat host are negatively affected by the host immune response, such that a month after infection, worms are lost from the hosts. Here we have investigated the changes in parasite gene expression that occur as the anti-S. ratti immune pressure increases. Existing S. ratti expressed sequence tags were used to construct a microarray consisting of 2227 putative genes. This was probed with cDNA prepared from parasites subject to low or high immune pressures. There are significant changes in the gene expression of S. ratti when subject to different immune pressures. Most of the genes whose expression changes have no significant alignment to known genes. These data together with previous S. ratti EST data were then used to identify genes that we hypothesise are central to the parasitic life of S. ratti and, perhaps, other parasitic nematodes. These analyses have identified genes likely to play a key role in the parasitic life of S. ratti; these genes should be the priority for further investigation.     

Association of Rhinovirus Infections with Asthma

Rhinoviruses are the most common cause of the common cold, but they can cause more severe illnesses in people with underlying lung disorders such as asthma, chronic obstructive pulmonary disease, or cystic fibrosis. Epidemiologic studies with sensitive detection methods such as PCR have identified rhinovirus infection as a major source of asthma exacerbations in both children and adults, especially during the spring and fall. Since rhinoviruses cause little tissue destruction, it is presumed that the immune response to the infection may play an important role in the pathogenesis of rhinovirus-induced exacerbations of asthma. This review examines the epidemiologic association between rhinovirus infections and exacerbations of asthma and outlines current information on immune responses to rhinovirus infection and potential connections between antiviral responses and preexisting allergic inflammation. Finally, current and future strategies for treating rhinovirus infections and virus-induced exacerbations of asthma are discussed.     

Intra-phylum and inter-phyla associations among gastrointestinal parasites in two wild mammal species

A growing body of literature reveals that the interactions among the parasite community may be strong and significant for parasite dynamics. There may be inter-specific antagonistic interactions as a result of competition and cross-effective immune response, or synergistic interactions where infection by one parasite is facilitated by another one, either by an impoverishment of the host’s defenses, parasite-induced selective immunosuppression, or trade-offs within the immune system. The nature of these interactions may depend on how related are the parasite species involved. Here we explored the presence of associations among gastrointestinal parasites (coccidia and helminths) in natural populations of two wild mammal species, the capybara (Hydrochoerus hydrochaeris) and the guanaco (Lama guanicoe). The associations explored were between the oocyst outputs of a selected Eimeria species and the other coccidia of that parasite community, and between Eimeria spp. and the predominant nematodes. The statistical analysis included adjustment for potential confounders or effect modifiers. In guanacos, the prevailing interactions were synergistic among the coccidia and between coccidia and nematodes (Nematodirus spp.). However, in capybaras, the interaction between nematodes (Viannaiidae) and Eimeria spp. depended on environmental and host factors. The relationship was positive in some circumstances (depending on season, year, sex, or animal size), but it appeared to become antagonistic under different scenarios. These antagonist interactions did not follow a particular seasonal pattern (they occurred in autumn, spring, and summer), but they were predominantly found in females (when they depended on sex) or in 2010 and 2011 (when they depended on the sampling year). These results suggest that the relationship between coccidia and nematodes in capybaras may be context dependent. We propose that the context-dependent immune investment documented in capybaras may be the cause of these varying interactions.     

The role of anti‐flavivirus humoral immune response in protection and pathogenesis

Flavivirus infections are a public health threat in the world that requires the development of safe and effective vaccines. Therefore, the understanding of the anti‐flavivirus humoral immune response is fundamental to future studies on flavivirus pathogenesis and the design of anti‐flavivirus therapeutics. This review aims to provide an overview of the current understanding of the function and involvement of flavivirus proteins in the humoral immune response as well as the ability of the anti‐envelope (anti‐E) antibodies to interfere (neutralizing antibodies) or not (non‐neutralizing antibodies) with viral infection, and how they can, in some circumstances enhance dengue virus infection on Fc gamma receptor (FcγR) bearing cells through a mechanism known as antibody‐dependent enhancement (ADE). Thus, the dual role of the antibodies against E protein poses a formidable challenge for vaccine development. Also, we discuss the roles of antibody binding stoichiometry (the concentration, affinity, or epitope recognition) in the neutralization of flaviviruses and the “breathing” of flavivirus virions in the humoral immune response. Finally, the relevance of some specific antibodies in the design and improvement of effective vaccines is addressed.     

APOPTOSIS PREVENTION AS A MECHANISM OF IMMUNE EVASION

When cells are infected with viruses, they may trigger their apoptosis programs. In unicellular organisms, this may have protected cell populations by limiting viral replication from infected cells. Multicellular organisms can also trigger the apoptosis program after viral infection. In response, viruses have evolved a wide variety of inhibitors of apoptosis. In higher organisms, the outcome of viral infections is largely determined by the immune system. Since apoptosis is intimately linked to the function and regulation of the immune system, the ability of viruses to inhibit apoptosis could profoundly alter the immune response. Viral antiapoptotic proteins could protect infected cells from apoptosis induced by cytotoxic lymphocytes, alter antigen cross-presentation and the priming of the immune response, or modulate the expression of danger signals from sites of infection. The virus/host interaction is likely to provide useful lessons regarding the workings of the mammalian immune system.     

Both free-living and parasitic nematodes induce a characteristic Th2 response that is dependent on the presence of intact glycans

Infection with parasitic nematodes is characterized by the induction of a profound type 2 immune response. We have studied the role of glycans in the induction of the skewed type 2 response by antigens of the parasitic nematode Brugia malayi as well as the free-living nematode Caenorhabditis elegans. Lymph node cells from BALB/c mice immunized with soluble extracts of the two nematodes showed distinct antigen-specific proliferation and cytokine production; however, both nematodes induced antigen-specific interleukin 4 (IL-4) production, demonstrating that the induction of a biased type 2 response is not unique to parasitic nematodes. Sodium periodate-treated soluble extracts of both nematodes consistently induced significantly less IL-4 production than the respective mock-treated extracts, indicating that glycans play a critical role in the induction of the Th2 immune response by these nematodes. The glycan-dependent induction of the Th2-potentiating cytokine IL-4 occurs by 72 h postinoculation. Our data suggest that glycan determinants common to nematodes act as ligands, displaying distinct molecular patterns that trigger the immune system to launch a biased Th2 immune response upon exposure to these organisms or their products. Further, the similarity of our findings to those for Schistosoma mansoni egg antigen is striking considering the enormous phylogenetic distance between nematodes and trematodes. These data thus have important implications for how the mammalian host responds to widely divergent metazoan invaders and suggest that the powerful C. elegans model system can be used to address these questions.     

Apoptosis prevention as a mechanism of immune evasion

When cells are infected with viruses, they may trigger their apoptosis programs. In unicellular organisms, this may have protected cell populations by limiting viral replication from infected cells. Multicellular organisms can also trigger the apoptosis program after viral infection. In response, viruses have evolved a wide variety of inhibitors of apoptosis. In higher organisms, the outcome of viral infections is largely determined by the immune system. Since apoptosis is intimately linked to the function and regulation of the immune system, the ability of viruses to inhibit apoptosis could profoundly alter the immune response. Viral antiapoptotic proteins could protect infected cells from apoptosis induced by cytotoxic lymphocytes, alter antigen cross-presentation and the priming of the immune response, or modulate the expression of danger signals from sites of infection. The virus/host interaction is likely to provide useful lessons regarding the workings of the mammalian immune system.     

Immunopathology of RSV infection: prospects for developing vaccines without this complication

Respiratory syncytial virus is the most important cause of lower respiratory tract infection in infants and young children. RSV clinical disease varies from rhinitis and otitis media to bronchiolitis and pneumonia. An increased incidence of asthma later in life has been associated with the more severe lower respiratory tract infections. Despite its importance as a pathogen, there is no licensed vaccine against RSV. This is due to a number of factors complicating the development of an effective and safe vaccine. The immunity to natural RSV infection is incomplete as re-infections occur in all age groups, which makes it challenging to design a protective vaccine. Second, the primary target population is the newborn infant, which has a relatively immature immune system and maternal antibodies that can interfere with vaccination. Finally, some vaccines have resulted in a predisposition for exacerbated pulmonary disease in infants, which was attributed to an imbalanced Th2-biased immune response, although the exact cause has not been elucidated. This makes it difficult to proceed with vaccine testing in infants. It is likely that an effective and safe vaccine needs to elicit a balanced immune response, including RSV-specific neutralising antibodies, CD8 T-cells, Th1/Th2 CD4 T-cells and preferably secretory IgA. Subunit vaccines formulated with appropriate adjuvants may be adequate for previously exposed individuals. However, intranasally delivered genetically engineered attenuated or vectored vaccines are currently most promising for newborns, as they are expected to induce a balanced immune response similar to that elicited to natural infection and not be subject to interference from maternal antibodies. Maternal vaccination may be the optimal strategy to protect the very young infants.     

Forward genetic dissection of innate response to infection in inbred mouse strains: selected success stories

Mouse genetics is a powerful tool for the dissection of genes, proteins, and pathways important in biological processes. Application of this approach to study the host response to infection has been a rich source of discoveries that have increased our understanding of the early innate pathways involved in responding to microbial infections. Here we review some of the key discoveries that have arisen from pinpointing the genetic defect in mouse strains with unusual or extreme response to infection and have led to insights into pathogen sensing pathways and downstream effector functions of the early innate immune response.     

Immunity to salmonellosis

Salmonella enterica is a genetically broad species harboring isolates that display considerable antigenic heterogeneity and significant differences in virulence potential. Salmonella generally exhibit an invasive potential and they can survive for extended periods within cells of the immune system. They cause acute or chronic infections that can be local (e.g. gastroenteritis) or systemic (e.g. typhoid). In vivo Salmonella infections are complex with multiple arms of the immune system being engaged. Both humoral and cellular responses can be detected and characterized, but full protective immunity is not always induced, even following natural infection. The murine model has proven to be a fertile ground for exploring immune mechanisms and observations in the mouse have often, although not always, correlated with those in other infectable species, including humans. Host genetic studies have identified a number of mammalian genes that are central to controlling infection, operating both in innate and acquired immune pathways. Vaccines, both oral and parenteral, are available or under development, and these have been used with some success to explore immunity in both model systems and clinically in humans.     

Caenorhabditis elegans immune conditioning with the probiotic bacterium Lactobacillus acidophilus strain NCFM enhances gram-positive immune responses

Although the immune response of Caenorhabditis elegans to microbial infections is well established, very little is known about the effects of health-promoting probiotic bacteria on evolutionarily conserved C. elegans host responses. We found that the probiotic Gram-positive bacterium Lactobacillus acidophilus NCFM is not harmful to C. elegans and that L. acidophilus NCFM is unable to colonize the C. elegans intestine. Conditioning with L. acidophilus NCFM significantly decreased the burden of a subsequent Enterococcus faecalis infection in the nematode intestine and prolonged the survival of nematodes exposed to pathogenic strains of E. faecalis and Staphylococcus aureus, including multidrug-resistant (MDR) isolates. Preexposure of nematodes to Bacillus subtilis did not provide any beneficial effects. Importantly, L. acidophilus NCFM activates key immune signaling pathways involved in C. elegans defenses against Gram-positive bacteria, including the p38 mitogen-activated protein kinase pathway (via TIR-1 and PMK-1) and the β-catenin signaling pathway (via BAR-1). Interestingly, conditioning with L. acidophilus NCFM had a minimal effect on Gram-negative infection with Pseudomonas aeruginosa or Salmonella enterica serovar Typhimurium and had no or a negative effect on defense genes associated with Gram-negative pathogens or general stress. In conclusion, we describe a new system for the study of probiotic immune agents and our findings demonstrate that probiotic conditioning with L. acidophilus NCFM modulates specific C. elegans immunity traits.     

Mast cells in the eyes of Calomys callosus(Rodentia: Cricetidae) infected by Toxoplasma gondii

The mast cell is a powerful effector cell for the innate immune system, acting through the secretion of several distinct mediators. Few studies have demonstrated the relationship between mast cells and toxoplasmosis. In this study, mast cells were investigated in two experimental Toxoplasma infections using Calomys callosus (Rodentia: Cricetidae) as the host.Animals were inoculated either intraperitoneally or via the conjunctiva with tachyzoites of Toxoplasma gondii (RH strain) and sacrificed after 5 days or 24 h, respectively. Enucleated eyes were processed for histological and ultrastructural analysis. Neither experimental infection altered the localization of mast cells compared to control eyes, but they did lead to an accumulation in some tissues as well as to their activation. There was a significant increase in the number of mast cells within 5 days and 24 h after infection. The ocular lesions were characterized by the presence of tachyzoites, inflammatory cells and vasodilatation in the iris and retina. In conclusion, mast cells were mobilized in these experimental infections, suggesting that they play an important role in the host inflammatory response after infection with T. gondii.     

Costimulatory TNFR family members in control of viral infection: Outstanding questions

Members of the TNFR family can play prominent roles in controlling the magnitude, duration and phenotype of the immune response to viruses. The importance of particular TNFRs in different viral infections and whether they contribute to viral control or pathology is dependent on the virus and the severity of the infection. TNFRs and their ligands are widely and differentially expressed on both adaptive and innate immune cell types. The cell types through which TNFRs exert their effects, the unique signals provided by each member of the family, and how these signals are ultimately integrated during an anti-viral immune response remain to be fully elucidated. Here we discuss the role of 4-1BB, OX40, CD27 and GITR and their ligands during viral infection and highlight some of the outstanding questions in the field.     

Immunity and resistance to astrovirus infection

Astroviruses are one of the leading causes of acute viral enteritis in infants, and are recognized as a clinically important pathogen in the elderly and the immunocompromised. In spite of this, we still know very little about the immune response to astrovirus infection. Clinical observations and human volunteer studies have indicated a role for the humoral response and suggest neutralizing antibodies are important in limiting infection. Studies of human intestinal biopsies have suggested that cellular immunity; specifically CD4(+) T-cells may also be involved in the anti-astrovirus response. Additionally, various animal models have indicated potential roles for the innate immune system in controlling infections. How these various effector arms of the immune system collaborate to result in immunity and resistance to astrovirus infection is still unknown. This review summarizes our current understanding of the immune response to this pathogen and highlights the key concepts that still need to be addressed. Until we understand the role of the immune system in astrovirus infection or other enteric viruses, we will continue to be limited in our ability to treat and control gastrointestinal diseases.     

Regulatory T cells in virus infections

Summary: This review discusses situations when the magnitude and function of immune responses to virus infection are influenced by regulatory T cells (Tregs). The focus is on CD4⁺CD25⁺ forkhead box protein 3⁺ natural Tregs (nTregs). The immune response may be limited in magnitude and efficacy when animals with normal nTreg function are infected with virus. This limitation can be observed both in vitro and in vivo. In the case of herpes simplex virus (HSV), animals depleted of nTregs prior to infection more effectively control the virus. With some virus infections, Treg responses (either nTregs or interleukin‐10‐dependent adaptive Tregs) appear to contribute to immune dysfunction, accounting for viral persistence and chronic tissue damage. This may occur with hepatitis C virus and some retrovirus infections that include human immunodeficiency virus (HIV). Under other circumstances, the nTreg response is judged to be beneficial, as it may help limit the severity of tissue damage associated with an immunoinflammatory reaction to virus infection. Such a situation occurs in HSV‐induced immunopathological lesions in the eye. With HIV, nTregs may help limit chronic immune activation that may precede collapse of the immune system. This review also discusses how virus infections become recognized by nTreg responses and how such responses might be manipulated to increase immunity or to limit virus‐induced immunopathology.     

Cutaneous defenses against dermatophytes and yeasts.

Predispositions to the superficial mycoses include warmth and moisture, natural or iatrogenic immunosuppression, and perhaps some degree of inherited susceptibility. Some of these infections elicit a greater inflammatory response than others, and the noninflammatory ones are generally more chronic. The immune system is involved in the defense against these infections, and cell-mediated immunity appears to be particularly important. The mechanisms involved in generating immunologic reactions in the skin are complex, with epidermal Langerhans cells, other dendritic cells, lymphocytes, microvascular endothelial cells, and the keratinocytes themselves all participating in one way or another. A variety of defects in the immunologic response to the superficial mycoses have been described. In some cases the defect may be preexistent, whereas in others the infection itself may interfere with protective cell-mediated immune responses against the organisms. A number of different mechanisms may underlie these immunologic defects and lead to the development of chronic superficial fungal infection in individual patients. Although the immunologic defects appear to be involved in the chronicity of certain types of cutaneous fungal infections, treatment of these defects remains experimental at the present time.