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Genetics influence susceptibility to Kala-azar

Padmini K

Leishmaniasis results from the bite of infected sandflies. New research indicates that genetic make-up could impact how individuals respond to kala-azar, the most severe form of leishmaniasis.

A Phlebotomus papatasi sand fly
A Phlebotomus papatasi sand fly   (Photo: Centers for Disease Control and Prevention's Public Health Image Library (PHIL), with identification number #10277)

When it is time for the female sand fly to hatch her eggs, a nutrient-rich blood meal is an immediate necessity. That means a bite into the nearest mammal or rodent. A sand fly infected with parasitic Leishmania can, during the bite, infect its host, causing the onset of Leishmaniasis. According to the 2014WHO fact sheet, the disease occurs mainly in 3 forms: Cutaneous, Mucocutaneous and Visceral Leishmaniasis (VL). VL also known as kala-azar (black fever) is the severest of these. Accompanied by fever and ulcers, VL can damage the vital organs (liver, spleen) over time and potentially result in death if left untreated.

recent article in Parasitology International from Kumarasamy Thangaraj’s lab at Center of Cell and Molecular Biology (CCMB) Hyderabad examines the connection between VL caused by the parasitic protozoa Leishmania donovani and the serum protein Mannose Binding Lectin (MBL). MBL is a blood protein that upon encountering foreign bodies (bacteria, protozoa, fungi or virus), binds to them and activates the complement lectin cascade’ — the body’s first mechanism of elimination of infectious gatecrashers. MBL is known to affect Brazilian VL caused by L chagassi. In order to examine the effects of MBL on Indian VL caused by L donovani, Thangaraj’s team conducted a case-controlled study in Bihar, which is an established hotspot for VL. Based on medical records issued by Government Hospitals, 443 subjects were recruited (218VL patients and 225 healthy controls). Genomic DNA extracted from blood samples were PCR-amplified and sequenced to identify the variants in MBL2 gene and quantify MBL protein levels. 

The MBL serum levels in VL patients were significantly higher compared to those in healthy cases. This is in sync with previous studies that indicate higher MBL levels during intracellular infections. Genetic analysis by the researchers has demonstrated that the promoter region of MBL2 gene (78th position) is an important genetic factor for VL occurrence — the presence of a specific variant decreased the susceptibility to the disease. Further higher degree genetic analysis clarified that some genetic segments occur more frequently in healthy subjects, suggesting a correlation with a reduced risk of VL. Interestingly, MBL2 variants have shown different effects in the context of other intracellular infections in other regions of the world. For instance, MBL2*LUPA haplotype is identified as an important risk factor in Brazilian patients with leprosy. Thus it is possible that the role of MBL2 variants differ with different­ geographical settings.

VL is a global health burden with 4,00,000 new cases and 40,000 deaths reported worldwide. A whopping 67% of this global disease burden is shared by India, where VL is a major endemic disease especially in the states of Bihar, West-Bengal and Eastern UP — they account for 90% of Indian VL. VL is treatable, and minimizing exposure to sandflies through covered clothing and careful use of insect-repellants is the best precaution. The lead author Anshuman Mishra, a postdoc at CCMB, who was involved with the yearlong effort of identifying patients in Bihar, notes that lack of hygiene is an important contributor to the continuous presence of VL. However, on a preventive note, there are no vaccines available for human use up to date and this underlines the importance of ongoing research in this area. The findings from this study indicate that the severity of VL in infected patients might differ depending on the genetic variations in MBL2, thus adding a new dimension to the current scientific understanding of Kala-azar.

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