Some aspects of protozoan infections in immunocompromised patients- a review

Protozoa are among the most important pathogens that can cause infections in immunocompromised hosts. These microorganisms particularly infect individuals with impaired cellular immunity, such as those with hematological neoplasias, renal or heart transplant patients, patients using high doses of corticosteroids, and patients with acquired immunodeficiency syndrome. The protozoa that most frequently cause disease in immunocompromised patients are Toxoplasma gondii, Trypanosoma cruzi, different Leishmania species, and Cryptosporidium parvum; the first two species cause severe acute meningoencephalitis and acute myocarditis, Leishmania sp. causes mucocutaneous or visceral disease, and Cryptosporidium can lead to chronic diarrhea with hepatobiliary involvement. Various serological, parasitological, histological and molecular methods for the diagnosis of these infections are currently available and early institution of specific therapy for each of these organisms is a basic measure to reduce the morbidity and mortality associated with these infections.     

Immunotherapy for fungal infections

Invasive fungal infections have become a major cause of mortality in immunocompromised individuals. Despite the current availability of number of highly active antifungal agents, overall mortality remains around 40%. Importantly, it is clear that a failure to restore host immunity leads to worse outcomes. These observations provide clear rationale for the development of novel immunotherapies to improve outcomes in immunocompromised individuals with invasive fungal infections. In this article we summarise the key advances that have been made in the field of immunotherapy for fungal infections in recent years, with a particular focus on clinical studies of interferon-γ therapy, adoptive T cell therapy, and gene therapy for chronic granulomatous disorder. In addition a number of pre-clinical approaches are reviewed.     

Immunomodulators as an antimicrobial tool

The spectrum of infectious diseases has shifted in the past 50 years to include those caused by microbes that cause disease predominantly in immunocompromised individuals. This phenomenon has underscored the dependence of microbial virulence on the immune status of the host. The limited efficacy of the available antimicrobial armamentarium in immunocompromised individuals, combined with increasing resistance to these agents, has led to an urgent need for new therapies for infectious diseases. Immunomodulation represents a novel approach to antimicrobial therapy that depends on bolstering host immunity, rather than direct antimicrobial activity. Immunomodulators can be divided into those that are specific to pathogens (pathogen-specific) and those that are not specific to pathogens (non-specific). However, to date only a few immunomodulators have been evaluated for their efficacy as antimicrobial tools.     

Adenoviruses in medicine: innocuous pathogen,predator, or partner

The consequences of human adenovirus (HAdV) infections are generally mild. However, despite the perception that HAdVs are harmless, infections can cause severe disease in certain individuals, including newborns, the immunocompromised, and those with pre-existing conditions, including respiratory or cardiac disease. In addition, HAdV outbreaks remain relatively common events and the recent emergence of more pathogenic genomic variants of various genotypes has been well documented. Coupled with evidence of zoonotic transmission, interspecies recombination, and the lack of approved AdV antivirals or widely available vaccines, HAdVs remain a threat to public health. At the same time, the detailed understanding of AdV biology garnered over nearly 7 decades of study has made this group of viruses a molecular workhorse for vaccine and gene therapy applications.     

Use of antibiotics in the management of postirradiation wound infection and sepsis

Ionizing gamma irradiation depresses the host defenses and enhances the susceptibility of the immunocompromised host to local and systemic infection due to endogenous or exogenous microorganisms. Trauma and wounding act synergistically and decrease the survival after exposure to irradiation. The current antimicrobial agents suitable for controlling serious infections and their use in post irradiation local and systemic infection with and without trauma are discussed. The experience gained in managing immunocompromised patients following chemotherapy is reviewed. Empiric single agent or combination agent therapy should be directed at the eradication of potential gram-negative as well as gram-positive pathogens. The most important organisms known to cause these infections are Pseudomonas sp. and Enterobacteriaceae. Management of intra-abdominal infections following trauma should include early surgical correlation and antimicrobials directed against the Bacteroides fragilis group and Enterobacteriaceae. Staphylococcus aureus and Streptococcus pyogenes cause most skin and soft tissue infections following trauma. Chemoprophylaxis of enteric sources of systemic infection can be achieved by antimicrobials that selectively inhibit the Enterobacteriaceae sp. and preserve the anaerobic flora. The management of infection in the injured and irradiated host includes supportive and restorative therapy. Supportive therapy includes débridement and cleansing of wounds, fluids, immunoglobulin, and antimicrobials. Restorative therapy includes definite surgery repair and replenishment of the immune system by use of immunomodulators, growth factors, and bone marrow transplantation. Further studies are needed to examine the usefulness of presently available drugs and experimental agents in the irradiated and traumatized host.     

Malassezia Species: A Rare Cause of Invasive Fungal Infections in Immunocompromised Patients

The members of Malassezia species, which may cause skin disorders in healthy individuals, are associated with both cutaneous and systemic disorders in immunocompromised patients. These disorders include folliculitis, seborrheic dermatitis, catheter-related fungemia, and deeply invasive infections. This review examines not only the risk factors and pathogenesis of this rare fungal infection but also the clinical manifestations, diagnosis, and treatment of Malassezia infections in immunocompromised patients. Reports from several series of immunocompromised patients have shown low mortality rates with appropriate treatment.     

The Role of Human IL-17 Immunity in Fungal Disease

Candida species are major causes of invasive and mucocutaneous fungal infections. Various recognition pathways and effector mechanisms are involved in triggering intrinsic, innate and adaptive host immune responses to these fungi. Invasive candidiasis may involve almost any internal organ or anatomic site and is a significant cause of morbidity and mortality in immunocompromised individuals, including, in particular, those with primary immunodeficiency disorders (PIDs) affecting phagocytic cells. Other PIDs characterized by an impairment of IL-17 T cell-mediated immunity confer predisposition to mucocutaneous Candida infections, with Candida albicans in particular. We discuss here inborn errors of immunity leading to an impairment of IL-17-mediated host defense and the occurrence of mucocutaneous candidiasis.     

Rare Fungal Infections in Children: An Updated Review of the Literature

An increasing trend of reports of rare fungal diseases has been observed to be mainly associated with the substantial increase of high-risk immunocompromised children, as well as with the selective pressure of antifungal drugs. On the other hand, recent reports have shown that several species of these rare fungi may also cause infections in immunocompetent children without obvious underlying conditions. The clinical spectrum of these infections, and most importantly their outcome, varies greatly, implying for a rather heterogenic group of pediatric infections. Various types of superficial and subcutaneous fungal infections, as well as systemic and disseminated life-threatening infections, have been reported. Prompt diagnosis and appropriate treatment of rare fungal diseases in children remains a great challenge. Several treatment options have been used, ranging from localized to combination treatment with extensive surgical excision and long-term antifungal therapy. We review contemporary data of rare fungal infections in pediatric patients focusing on epidemiology, mycology, management and outcome, published during the last three years.     

Secondary Infections,Expanded Tissue Tropism,and Evidence for Malignant Potential in Immunocompromised Mice Infected with Mus musculus Papillomavirus 1 DNA and Virus

Papillomavirus disease poses a special challenge to people with compromised immune systems. Appropriate models to study infections in these individuals are lacking. We report here the development of a model that will help to address these deficiencies. The MmuPV1 genome was synthesized and used successfully to produce virus from DNA infections in immunocompromised mice. In these early studies, we have demonstrated both primary and secondary infections, expanded tissue tropism, and extensive dysplasia.     

Harmful fungi in both agriculture and medicine

Most fungi are saprophytic and not pathogenic to plants, animals and humans. However, a relative few fungal species are phytopathogenic, cause disease (e.g., infections, allergies) in man, and produce toxins that affect plants, animals and humans. Among such fungi are members of the Aspergillus and Fusarium genera as well as other genera (e.g., Alternaria, Mucor) comprising the emerging pathogen group in humans. These fungi present a common threat to both agricultural production and the health of healthy and immunocompromised individuals. Taken together, these relative few fungi can cause huge economic losses to agriculture, loss of food for consumption, and serious, often fatal diseases in humans and animals. Plants may be a source of antifungal compounds since they have had to develop compounds to resist infections by fungi present in their environment.     

Effects of biological and non-biological immunomodulatory therapies on the immunogenicity of vaccines in patients with rheumatic diseases

Vaccinations are administered to patients to induce a protective immune response, resulting in immunological memory. Preventing infection through the use of vaccines is particularly important in immunocompromised and immunosuppressed individuals given their increased frequency and severity of infections relative to healthy individuals. Recent surveys show that the vaccination rate is still alarmingly low in patients with rheumatic disease. In this review we briefly discuss the different types of vaccines and then critically examine evidence related to vaccination efficacy in patients with autoimmune disease and the effects of immunomodulatory therapy, with an aim to provide guidance and optimize the administration of vaccines in such individuals.     

C-type lectin receptors and cytokines in fungal immunity

Fungi are the cause of opportunistic infections, predominantly in immunocompromised individuals although, primary fungal infections can occur in apparently healthy individuals. Successful host defence requires an effective innate and adaptive immune response. Central to host immune responses are the induction of cytokines; the signals which help to activate the innate immune system and which play a central role in directing the development of pathogen-specific immunity. C-type lectins play a central role in the recognition and shaping of immune responses to fungal pathogens, in part, through the induction and modulation of cytokine responses. Understanding which cytokines induce protective responses to these pathogens and how C-type lectins and other receptors direct cytokine production may allow development of novel antifungal therapies. Here we review the C-type lectins, their influence on cytokine production and subsequent immune responses in antifungal immunity.     

Use of Voriconazole for the Treatment of Paecilomyces lilacinus Cutaneous Infections: Case Presentation and Review of Published Literature

The fungus Paecilomyces lilacinus is a rare but emerging pathogen that causes severe human infections, especially in immunocompromised hosts. It is an important organism to identify due to its poor susceptibility to conventional antifungal drugs, including amphotericin B, itraconazole, and fluconazole. Oculomycosis and cutaneous infections are the two most common manifestations of P. lilacinus infections. Voriconazole has been used successfully to treat P. lilacinus endophthalmitis, but reports of skin and soft tissue infections treated with voriconazole are limited to six prior publications. Our immunocompromised patient had a subcutaneous P. lilacinus infection successfully treated with 3 months of voriconazole therapy.     

Recommendations for fungal opportunistic infections prevention in persons infected with human immunodeficiency virus

Fungal infections have become important causes of morbidity and mortality in immunocompromised hosts, including those with the acquired immune deficiency syndrome (AIDS). Although significant therapeutic advances are being made in the field of antiretroviral therapy, parallel advances must be attained in the management of secondary infections, including those due to fungi. As increasing numbers of people with HIV infection come in to medical attention, the problem of fungal infections will also increase, requiring innovative approaches toward understanding the pathogenesis of these infections and developing new diagnostic and therapeutic modalities. A better understanding is required for the immunopathogenesis of fungal infections. Improved understanding of new and established antifungal agents in conjunction with ART agents as well as immune modulators, should yield important advances in prevention, control and treatment of fungal infections of HIV infected people.     

Treatment options in emerging mold infections

Although Zygomycetes, Fusarium spp, and Scedosporium spp are far less frequent causes of invasive fungal disease than Aspergillus and Candida, they are emerging. These types of infections in severely immunocompromised patients have a common feature: a poor clinical response to antifungal therapy. Infection is usually airborne, although local infections in cases of skin trauma are also possible. These fungi are resistant to some common antifungal agents; therefore, surgical debridement of the necrotic tissue, when possible, should be combined with specific systemic antifungal treatment in immunocompromised patients. In the absence of randomized clinical trials, most experience in the treatment of these infections is with amphotericin B. Experience with new antifungal agents is still limited, and recovery from neutropenia remains the main predictor of a favorable outcome.     

Current Diagnosis and Management of Mucormycoses

Due to the rising incidence of diabetes mellitus, the increasing populations of immunocompromised individuals of varied etiologies, and the progresses that have been made in the management of the critically ill, the incidence of invasive fungal infections, in particular those caused by the Mucorales, is increasing. Currently available diagnostics frequently miss this infection. Knowledge of the factors placing individuals at risk for and the varied clinical presentations of mucormycosis should alert clinicians of the possible presence of this infection. Survival of individuals with mucormycosis is dependant on prompt diagnosis and aggressive therapy with antifungal agents; surgical debridement; and, if possible, reversal of the risk factors predisposing the individual to this infection. It is hoped that improved diagnostic testing, improvements in pharmacotherapy, and adjunctive therapies will improve the morbidity and mortality of mucormycosis.     

A role of some food arthropods as vectors of human enteric infections

Arthropods are very important organisms in the environment in relation to transmission of pathogenic infections to humans. The information on transmission of pathogenic infections to people by commercially offered food arthropods is scant. Consumption of seafood is a very popular dietary habit around the world. Whereas shrimp are the most commonly consumed seafood item, crabmeat has recently become a very popular commercial product, specifically for a majority of European countries. The transmission of waterborne protozoan parasites is facilitated by consumption of seafood harvested from contaminated waters, drinking water or via contact with recreational and surface waters, and remains common throughout the developing as well as the developed world. Protozoan infections pose a significant health risk for immunocompetent individuals, and may cause life-threatening diseases among immunocompromised and immunosuppressed individuals. The transmissive stages of human protozoan parasites are small in size and are shed in large numbers in feces of infected people and animals. These pathogens are resistant to environmental stressors (sometimes even to chlorine disinfection), and only a few of them (e.g., Cryptosporidium oocysts, Giardia cysts, or Vibrio bacteria) are able to cause infection in seafood consumers.     

Molecular Modeling of Mycobacterium Tuberculosis DNA Gyrase and its Molecular Docking Study with Gatifloxacin Inhibitors

Abstract

Mycobacterium tuberculosis (Mt) is a leading cause of infectious disease in the world today. This outlook is aggravated by a growing number of Mt infections in individuals who are immunocompromised as a result of HIV infections. Thus, new and more potent anti-tuberculosis agents are necessary. Therefore, DNA gyrase was selected as a target enzyme to combat Mt. In this work, the first three-dimensional molecular model of the hypothetical structures for the Mycobacterium tuberculosis DNA gyrase (mtDNAg) was elucidated by a homology modeling method. In addition, the orientations and binding affinities of some gatifloxacin analogs with those new structures were investigated. Our findings could be helpful for the design of new more potent gatifloxacin analogs.     

Development of a new real-time TaqMan PCR assay for quantitative analyses of Candida albicans resistance genes expression

Candida albicans is an important opportunistic pathogen that can cause serious fungal diseases in immunocompromised patients including cancer patients, transplant patients, and patients receiving immunosuppressive therapy in general, those with human immunodeficiency virus infections and undergoing major surgery. Its emergence spectrum varies from mucosal to systemic infections and the first line treatment is still based on fluconazole, a triazole derivate with a potent antifungal activity against most of C. albicans strains. Nevertheless the emergence of fluconazole-resistant C. albicans strains can lead to treatment failures and thus become a clinical problem in the management of such infections. For that reason we consider it important to study mechanisms inducing azole resistance and the possibilities to influence this process. In this work we give a short report on a real-time PCR (TaqMan) assay, which can be used for quantitative analyses of gene expression levels of MDR1, CDR1 and ERG11, genes supposed to contribute to development of the resistance mechanisms. We show some results achieved with that assay in fluconazole susceptible and resistant strains that confirm results seen earlier in experiments using Northern blot hybridisation and prove that the comparative DeltaCt method is valid for our system.