Drug treatment of microsporidiosis

doi:10.1054/drup.2000.0174

Drug Resistance Updates

Volume 3, Issue 6, December 2000, Pages 384-399

https://doi.org/10.1054/drup.2000.0174 Get rights and content

Abstract

Microsporidia are ubiquitous organisms that are emerging pathogens in humans. These are most likely zoonotic and/or waterborne infections. In the immunosuppressed host, such as those treated with immunosuppressive drugs or infected with human immunodeficiency virus particularly at advanced stages of the disease, microsporidia can produce a wide range of clinical diseases. The most common manifestation is gastrointestinal tract infection; however, encephalitis, ocular infection, sinusitis, myositis and disseminated infection have also been described. In addition, these organisms have been reported in immune competent individuals. Multiple genera are involved in these infections and different organisms can result in distinct clinical pictures. Differences in clinical and parasitologic response to various therapeutic agents have emerged from clinical, as well as in vitro and in vivo studies. Currently there are no precisely defined guidelines for the optimal treatment of microsporidial infections. This article reviews the available data on compounds with in vitro activity and/or in vivo efficacy for microsporidial infections.

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In vivo and in silico investigations on the efficacy of albendazole against Enterocytozoon hepatopenaei (EHP) infecting Penaeus vannamei
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The microsporidian Enterocytozoon hepatopenaei (EHP) is an intercellular spore former that causes hepatopancreatic microsporidiosis (HPM), a commercially important disease in Penaeus vannamei (white leg shrimp) farming. In this study, albendazole an inhibitor of β-tubulin polymerization in microsporidians was evaluated for its efficacy in reducing EHP infection in P. vannamei. EHP-infected shrimps were exposed to 1, 5, 10, 25, 50 and 75 mg L⁻¹ of albendazole and evaluated for the reduction in EHP DNA copy numbers at 3, 6, 9, 12, 15, 18, 21, 24 days post-exposure (dpe) by absolute quantitative real-time PCR (RT-qPCR) assay. The expressions of antioxidant enzyme genes viz., cytosolic manganese superoxide dismutase (cMnSOD), catalase (CAT) and glutathione peroxidase (GPx); haemolymph aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) were assessed at 24 dpe. A maximum of about 98% reduction in EHP DNA copies was observed in the shrimps treated with 75 mg L⁻¹ per day for 24 days. A significant upregulation in relative expressions of GPx genes and a downregulation cMnSOD and CAT genes were observed in shrimps exposed to 25, 50 and 75 mg L^‐1 at 24 dpe. A significant reduction in haemolymph AST and ALT levels was observed upon treatment with 25, 50 and 75 mg L⁻¹ at 24 dpe and there are no significant changes in ALP. A virtual molecular docking between albendazole and EHP encoded β-tubulin revealed a best binding interaction with the presence of 11 hydrogens bonds, multiple non-covalent bonds and a very much lower solvation-free energy gain of −15.6 kcal mol⁻¹ in the active sites of protein interactions. Thus, this study identified albendazole as a potential drug to control EHP infection in shrimp, which might help to combat the production losses caused by EHP.
The course of infection of Encephalitozoon cuniculi genotype I in mice possess combination of features reported in genotypes II and III
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Out of three genotypes of Encephalitozoon cuniculi (I–III) available for experimental studies, E. cuniculi genotype I remains the less characterized.
This study describes for the first time individual phases of microsporidiosis caused by E. cuniculi genotype I and efficacy of albendazole treatment in immunocompetent BALB/c and C57Bl/6 mice and immunodeficient SCID, CD4^−/− and CD8^−/− mice using molecular detection and quantification methods.
We demonstrate asymptomatic infection despite an intense dissemination of microsporidia into most organs within the first weeks post infection, followed by a chronic infection characterized by significant microsporidia persistence in immunocompetent, CD4^−/− and CD8^−/− mice and a lethal outcome for SCID mice. Albendazole application led to loss E. cuniculi genotype I infection in immunocompetent mouse strains, decreased spore burden by half in CD4^−/− and CD8^−/− mice, and prolongation of survival of SCID mice.
These results showed Encephalitozoon cuniculi genotype I infection extend and albendazole sensitivity was comparable to E. cuniculi genotype II, but the infection onset speed and mortality rate was similar to E. cuniculi genotype III. These imply that differences in the course of infection and the response to treatment depend not only on immunological status of the host, but also on the genotype causing the infection.
Enterocytozoon bieneusi of animals—With an ‘Australian twist’
2021, Advances in Parasitology
Citation Excerpt :
Albendazole inhibits microsporidian division by blocking the synthesis of tubulin during the process of mitosis (Conteas et al., 2000; Costa and Weiss, 2000; Desportes-Livage and Datry, 2005). This compound is used, for example, to treat Encephalitozoon infections in HIV patients (Bednarska et al., 2013; Didier et al., 2004), with rare side effects (Costa and Weiss, 2000; Groß, 2003). This drug appears to have a parasitostatic effect on E. bieneusi (see Blanshard et al., 1993; Conteas et al., 2000; Costa and Weiss, 2000; Didier, 2005; Didier et al., 2004; Horton, 2002) and it alleviates clinical signs (i.e. decreased defaecation frequency and volume in infected individuals) (Dieterich et al., 1994), but symptom-relapses are common following treatment (Blanshard et al., 1993; Costa and Weiss, 2000).
Enterocytozoon bieneusi is a microsporidian microorganism that causes intestinal disease in animals including humans. E. bieneusi is an obligate intracellular pathogen, typically causing severe or chronic diarrhoea, malabsorption and/or wasting. Currently, E. bieneusi is recognised as a fungus, although its exact classification remains contentious. The transmission of E. bieneusi can occur from person to person and/or animals to people. Transmission is usually via the faecal-oral route through E. bieneusi spore-contaminated water, environment or food, or direct contact with infected individuals. Enterocytozoon bieneusi genotypes are usually identified and classified by PCR-based sequencing of the internal transcribed spacer region (ITS) of nuclear ribosomal DNA. To date, ~ 600 distinct genotypes of E. bieneusi have been recorded in ~ 170 species of animals, including various orders of mammals and reptiles as well as insects in > 40 countries. Moreover, E. bieneusi has also been found in recreational water, irrigation water, and treated raw- and waste-waters. Although many studies have been conducted on the epidemiology of E. bieneusi, prevalence surveys of animals and humans are scant in some countries, such as Australia, and transmission routes of individual genotypes and related risk factors are poorly understood. This article/chapter reviews aspects of the taxonomy, biology and epidemiology of E. bieneusi; the diagnosis, treatment and prevention of microsporidiosis; critically appraises the naming system for E. bieneusi genotypes as well as the phylogenetic relationships of these genotypes; provides new insights into the prevalence and genetic composition of E. bieneusi populations in animals in parts of Australia using molecular epidemiological tools; and proposes some areas for future research in the E. bieneusi/microsporidiosis field.
Hemocytin facilitates host immune responses against Nosema bombycis
2020, Developmental and Comparative Immunology
Citation Excerpt :
Nowadays, more than 1400 species have been identified, around 700 species can infect insects and over 17 species in 9 genera are known to infect humans, especially immune-deficient individuals (Cali et al., 2005; Vavra and Lukes, 2013; Weiss, 1995). Although there are many studies about the host immune response against microsporidia, the involvement of hemocytin in the process has not been reported so far (Akiyoshi et al., 2007; Bacchi et al., 2002; Cislakova and Halanova, 2003; Costa and Weiss, 2000). Our study found that the expression and secretion of hemocytin were significantly up-regulated in silkworms after infection with N. bombycis, indicating that hemocytin in the silkworms responded to the invasion of N. bombycis.
Invertebrates lack an adaptive immune response and thus are reliant on their innate immune response for eliminating invading pathogens. The innate immune responses of silkworms against the pathogen Nosema bombycis include: hemocyte aggregation, melanization, antimicrobial peptides, etc. In our current study, we discovered that a silkworm hemostasis-related protein, hemocytin, is up-regulated after Nosema bombycis infection. This novel finding lead to our hypothesis that hemocytin participates in immune responses against N. bombycis. We investigated this hypothesis by analyzing the adhesive effects of hemocytin to invading N. bombycis, and the hemocytin-mediated hemocyte aggregation and hemolymph melanization. We showed that hemocytin can adhere to the surface of N. bombycis, which facilitates the agglutination of N. bombycis and hemocytes as well as the subsequent melanization. Moreover, when we utilize RNAi technology to decrease in vivo hemocytin expression, we found that the proliferation of N. bombycis within the host significantly increased. These results support our hypothesis that hemocytin exerts pro-inflammatory effects by facilitating pathogen agglutination, along with hemocyte aggregation and melanization, to combat N. bombycis. Our study is the first to determine a function of hemocytin in innate immunity against N. bombycis. Moreover, our findings are of great importance to provide potential targets for developing novel strategy against microsporidia infection.
Symptomatic respiratory Encephalitozoon cuniculi infection in renal transplant recipients
2019, International Journal of Infectious Diseases
Citation Excerpt :
However, the importance of proper diagnosis is highlighted by the fact that the treatment of microsporidia is limited and genus-specific. In the treatment of human microsporidiosis, albendazole and fumagillin are known to have the highest clinical efficacy (Costa and Weiss, 2000; Champion et al., 2010). Albendazole is the drug of choice for the treatment of intestinal, respiratory, and disseminated microsporidiosis caused by Encephalitozoon spp., but has limited efficacy against E. bieneusi (Costa and Weiss, 2000).
Encephalitozoon spp. and Enterocytozoon bieneusi are intracellular parasitic fungi from the phylum Microsporidia, which initially localize to the intestine. As opportunistic pathogens, Encephalitozoon spp. in particular can disseminate to the respiratory tract, among other locations. Patients on life-long immunosuppression are at higher risk of such infections, mostly symptomatic.
Sputum samples and bronchial washings from 72 renal transplant recipients and 105 patients with various respiratory diseases were screened for Encephalitozoon spp. and E. bieneusi by microscopic examination and genus-specific nested PCR followed by genotyping.
A total of 8.3% (6/72) of immunosuppressed renal transplant recipients and 1.9% (2/105) of patients with various respiratory diseases, both immunocompetent and immunosuppressed, were positive for respiratory microsporidial infection. All six transplant recipients were Encephalitozoon cuniculi-positive by PCR/sequencing and five of them suffered from respiratory symptoms. The presence of microsporidial spores was also confirmed microscopically in three of the transplant recipients. Of the two immunocompetent patients with various respiratory diseases, one had an E. cuniculi infection, while the second had an E. bieneusi infection.
Life-long immunosuppression in renal transplant recipients increases the risk of respiratory infection by E. cuniculi. Microsporidia should be screened in respiratory samples of these patients, particularly when they have respiratory symptoms.
Respiratory microsporidiosis caused by Enterocytozoon bieneusi in an HIV-negative hematopoietic stem cell transplant recipient
2018, International Journal of Infectious Diseases
Citation Excerpt :
Since fumagillin is not registered for human treatment in Poland and albendazole appears to be well-tolerated in immunocompromised patients, this drug was administered to the patient in the present case report. Nevertheless, treatment with albendazole has been shown to result in clinical improvement in up to 50% of patients infected with E. bieneusi in some studies (Costa and Weiss, 2000). Moreover, the presence of E. bieneusi persisted during treatment in all patients, but a decrease in pathogen burden has been observed (Dieterich et al., 1994).
A 23-year-old, HIV-negative woman who had undergone a hematopoietic stem cell transplantation was admitted to the hospital with respiratory failure and symptoms of bronchiolitis obliterans. A chest computed tomography scan revealed diffuse ground-glass opacification and fibrous plugs. Due to worsening respiratory failure despite treatment, ventilation was provided through a tracheostomy tube. Molecular examination of bronchoalveolar lavage and urine revealed Enterocytozoon bieneusi infection. After treatment with albendazole the patient gradually improved, but the pathogen was not eradicated and reappeared on follow-up examination. E. bieneusi belongs to the most clinically important microsporidial species infecting humans, mostly those who are immunocompromised. This fungus tends to infect enterocytes of the intestine, and there are limited studies concerning its extraintestinal location. This is the first report of a case of disseminated respiratory and urinary E. bieneusi infection in a transplant recipient.

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Regular ArticleDrug treatment of microsporidiosis

Abstract

Ophthalmology

Hum Pathol

Gastroenterology,

Gastroenterology

Lancet

Am J Ophthalmol

Am J Ophthalmol

Ophthalmology

Gastroenterology

Lancet

Advances in Parasitology

Parasitol Today

Eur J Protistol

Toxicol Appl Pharmacol

J Invertebr Pathol

Diarrhoea and malabsorption in Acquired Immune Deficiency Syndrome: a study of four cases with special emphasis on opportunistic protozoan infestations

Gut

Occurrence of a new microsporidian: Enterocytozoon bieneusi n.g., n.sp., in the enterocytes of a human patient with AIDS

J Protozol

Microsporidian hepatitis in the Acquired Immunodeficiency Syndrome

Ann Intern Med

A Case of Encephalitozoon cuniculi peritonitis in a patient with AIDS

Am J Clin Pathol

MMWR

Microsporidial keratoconjunctivitis in a patient with AIDS

Br J Opthalmol

Microsporidial keratitis

Ophthalmology Clinics of North America

Ocular microsporidiosis

The microsporidia and microsporidiosis (Murray Wittner, editor, and Louis M. Weiss, contributing editor)

Intestinal microsporidiosis as a cause of diarrhea in Human Immunodeficiency Virus-infected patients

Hum Pathol

Clinical significance of small-intestinal microsporidiosis in HIV-1-infected individuals

Lancet

Microsporidial disease in HIV-infected patients: A report of 42 patients and review of the literature

Scand J Infec Dis

Treatment with albendazole for intestinal disease due to Enterocytozoon bieneusi in patients with AIDS

J Infect Dis

Myositis due to Pleistophora (Microsporidia) in a patient with AIDS

Clin Infect Dis

Myositis associated with a newly described microsporidian, Trachipleistophora hominis in a patient with AIDS

J Clin Microbiol

Identification of a new nosema-like microsporidian associated with myositis in an AIDS patient

J Euk Microbiol

Brachiola vesicularum, N.G., N.Sp., a new microsporidium associated with AIDS and myositis

J Euk Microbiol

Microsporidia infection in patients with the Human Immunodeficiency Virus and unexplained cholangitis

N Eng J Med

Septata intestinalis N.G., N.Sp., an intestinal Microsporidian associated with chronic diarrhea and dissemination in AIDS patients

J Euk Microbiol

Clinical features of microsporidiosis in AIDS

Clin Infect Dis

Multiorgan microsporidiosis: report of five cases and review

Clin Infect Dis

The role of Microsporidia in the pathogenesis of HIV-related chronic diarrhea

Ann Intern Med

Immunologically confirmed disseminated asymptomatic Encephalitozoon cuniculi infection of the gastrointestinal tract in a patient with AIDS

Clin Infect Dis

Urethritis associated with disseminated microsporidiosis: clinical response to albendazole

Clin Infect Dis

Microsporidian sinusitis in patients with the Acquired Immunodeficiency Syndrome

Laryngoscope

Cerebral microsporidiosis due to Encephalitozoon cunuculi– reply to letter

N Engl J Med

Cerebral microsporidiosis due to Encephalitozoon cuniculi in a patient with Human Immunodeficiency Virus infection

N Engl J Med

Intestinal microsporidiosis occurring in two renal transplant recipients treated with mycophenolate mofetil

Transplantation

Vittaforma corneae N. Comb. for the human microsporidium Nosema corneum Shadduck, Meccoli, Davis & Font, 1990, based on its ultrastructure in the liver of experimentally infected athymic mice

J Euk Microbiol

Clinical syndromes associated with microsporidiosis

Advances in Parasitology,

Improved light-microscopical detection of microsporidia spores in stool and duodenal aspirates

N Engl J Med

Treatment of intestinal microsporidiosis with albendazole in patients with AIDS

AIDS

Disseminated microsporidiosis due to Septata intestinalis in patients with AIDS: clinical features and response to albendazole therapy

J Infect Dis

Regular Article
Drug treatment of microsporidiosis