Gene makes some HIV-infected patients more at risk for fungal disease
HIV-infected people who carry a gene for a specific protein face a 20-fold greater risk of contracting cryptococcal disease, according to a study published in mBio®, the online open-access journal of the American Society for Microbiology.
Cryptococcus neoformans is the most common cause of fungal meningitis among HIV-infected individuals. While the disease is a risk for everyone with HIV who has a very low level of CD4+ T cells, researchers have discovered that those with the gene for the protein FCGR3A 158V have an immune cell receptor that binds tightly to antibody-bound C. neoformans. Perversely, this tight binding by a vigilant immune system may mean the patient’s own immune system strength becomes a weakness when facing the fungus.
“We found that this high affinity Fc receptor polymorphism was very highly overrepresented in the patients that got cryptococcal disease,” says corresponding author Liise-anne Pirofski of the Albert Einstein College of Medicine & Montefiore Medical Center in The Bronx, New York. Patients with two copies of the high affinity Fc receptor gene had an almost 20-fold increased risk of contracting the disease.
“It’s surprising that a receptor involved with a higher capacity to bind immune complexes would be associated with susceptibility in patients with HIV,” says Pirofski, since phagocytosis of immune complexes is thought of as a mechanism for fighting invading microorganisms.
Differences among Fc gamma receptors (FCGR) have already been linked to cryptococcosis susceptibility among people who are not infected with HIV, but this new information sheds light on how these receptors could influence susceptibility in HIV patients, who are at elevated risk of developing cryptococcosis and are known to have high levels of antibodies to C. neoformans. FCGRs are proteins expressed on the outsides of different kinds of immune cells, including B lymphocytes, natural killer cells, macrophages, neutrophils, and mast cells. They bind to antibodies that have grabbed onto invading pathogens, then stimulate the immune cells to destroy the invaders.
The researchers performed PCR-based genotyping on banked samples from 164 men enrolled in the Multicenter AIDS Cohort Study (MACS), including 55 who were HIV-infected and developed cryptococcal disease, a control group of 54 who were HIV-infected and 55 who were HIV-uninfected. After correcting for a number of factors like demographics and T cell counts, they found a strong association between the gene for the high-affinity FCGR3A 158V allele and the risk of cryptococcal disease in HIV-infected men.
To figure out what that meant, they followed up with binding studies and showed that cells that express FCGR3A 158V bind more strongly to antibody-C. neoformans complexes. Greater affinity for the antibody-C. neoformans complex could increase the attachment of the fungus to monocytes or macrophages, which could in turn increase the numbers of fungi living and replicating inside immune cells. And there’s also the possibility that these infected immune cells could act like a Trojan horse, delivering C. neoformans cells across the blood-brain barrier and allowing them to infect the brain. Pirofski says these possibilities are now under investigation.
C. neoformans is found all over the environment and studies show that nearly everyone is exposed to the fungus during their lifetime. However, the organism rarely causes disease in healthy people, but strikes most often in people with weakened immune systems. It is the main cause of fungal meningitis in people living with HIV, and causes devastating disease in those with profound CD4+ T cell deficiency.
People living with HIV get sick for one reason; opportunistic infections. There are several types of opportunistic infections that we have to be concerned with. One such type is fungal opportunistic infections. These infections can range from a mild nuisance to life threatening. Here is a guide to the most common fungal opportunistic infections.
Candidiasis
This is a form of yeast fungal infection and are of three types.
oral (thrush)
esophageal
vaginal
But not everyone with serious T cell deficiency develops cryptococcosis, and there is currently no way of knowing which patients will develop disease. Pirofski says a test that could distinguish who is most at risk has the potential to save countless lives, particularly in sub-Saharan Africa, which is home to 69% of all people living with HIV.
“This could be the beginning of a predictive test, at least in high-risk people” says Pirofski. “I think that we’re ready to study this receptor further as a risk factor for disease in larger cohorts.”
Oral Candidiasis
Like hairy leukoplakia, oral candidiasis is highly prevalent in HIV-infected individuals. Approximately 30% of otherwise asymptomatic gay men have one or both of these lesions, and they are often the first clinical expression of HIV disease. Three presentations of oral candidiasis are seen in association with HIV infection: pseudomembranous candidiasis (thrush), erythematous candidiasis, and angular cheilitis.
Pseudomembranous candidiasis appears as creamy, white, removable plaques that can be found anywhere in the mouth or pharynx. These plaques are caused by overgrowth of fungal hyphae mixed with desquamate epithelium and inflammatory cells.
Erythematous candidiasis presents as flat, subtle, red patches of varying sizes on any mucosal surface, commonly the palate and dorsal surface of the tongue. These two forms of oral candidiasis are equally predictive of the development of AIDS. Angular cheilitis involves fissuring and cracking at the corners of mouth. Occasionally, all three types appear in the same individual. The diagnosis of oral candidiasis is usually made from the appearance of the lesions, but the presence of hyphae and blastospores, seen on smears examined with potassium hydroxide or Gram stain, can help confirm the diagnosis.
Oral candidiasis may be treated with either topical or systemic antifungal agents. The choice of medication depends on a variety of factors, including other, concomitant medications, evidence of abnormal liver function, patient preference and compliance, and the sugar content of topical preparations. Topical agents include nystatin oral pastille, one or two pastilles dissolved slowly four to five times a day; clotrimazole oral troche, 10 mg, one troche dissolved five times a day; and nystatin oral suspension. Nystatin oral suspension has a high sugar content and its relatively short time in contact with the oral mucosa makes it less effective. If used for a long time, the oral topical agents that contain sweetening agents may promote caries, so daily topical fluoride rinses should be used in conjunction with long-term therapy. Other preparations that can be used topically for oral candidiasis include some vaginal preparations: nystatin vaginal troche 100,000 units, one troche dissolved in the mouth three times a day; or clotrimazole vaginal troche, one dissolved in the mouth daily.
Oral candidiasis can be treated systemically with ketoconazole, fluconazole, and itraconazole. Ketoconazole is used as one or two 200-mg tablets taken daily with food. However, since ketoconazole depends on normal levels of gastric acidity for its absorption and many HIV-infected patients have hypochlorhydria, caution should be exercised. Fluconazole is used as one 100-mg tablet taken once daily. Itraconazole is used as two 100-mg capsules taken daily. Oral candidiasis outbreaks often recur and maintenance therapy may be needed.
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mBio® is an open access online journal published by the American Society for Microbiology to make microbiology research broadly accessible. The focus of the journal is on rapid publication of cutting-edge research spanning the entire spectrum of microbiology and related fields. It can be found online at http://mbio.asm.org.
The American Society for Microbiology is the largest single life science society, composed of over 39,000 scientists and health professionals. ASM’s mission is to advance the microbiological sciences as a vehicle for understanding life processes and to apply and communicate this knowledge for the improvement of health and environmental and economic well-being worldwide.
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Jim Sliwa
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202-942-9297
American Society for Microbiology