Elsevier

Experimental Parasitology

Volume 106, Issues 1–2, January–February 2004, Pages 30-36
Experimental Parasitology

Isonicotinic acid hydrazide: an anti-tuberculosis drug inhibits malarial transmission in the mosquito gut

https://doi.org/10.1016/j.exppara.2004.01.002Get rights and content

Abstract

We studied the transmission-blocking effect of isonicotinic acid hydrazide (INH), a widely used anti-tuberculosis drug, against Plasmodium gallinaceum and Plasmodium berghei. INH-treatment of infected animals did not inhibit parasite development in the blood of the vertebrate host, but did inhibit exflagellation, ookinete formation, and oocyst development in the mosquito. Oocyst development was inhibited in a dose-dependent manner. The ED50 in the P. gallinaceum/chicken/Aedes aegypti model and P. berghei/mouse/Anopheles stephensi model was 72 and 109 mg/kg, respectively. In marked contrast, in vitro exflagellation and ookinete development were not directly affected by physiological concentrations of INH. We suggest that INH exerts its inhibitory effects on the mosquito stages of the malaria parasite by an indirect, and at present undefined mechanism. Further elucidation of the mechanism how INH inhibits parasite development specifically on mosquito stages may allow us to identify new targets for malaria control strategy.

Index Descriptors and Abbreviations: Plasmodium berghei; Plasmodium gallinaceum; Anopheles stephensi; Aedes aegypti; Transmission-blocking anti-malarial; INH, isonicotinic acid hydrazide; XA, xanthurenic acid; GAF, gametocyte activating factor; HBSA, Hepes-buffered suspended animation medium; EI, exflagellation index; ED50, half-maximal effective dose

Introduction

Due to the rapid emergence and spread of drug-resistant malaria (Wongsrichanalai et al., 2002; World Health Organization, 2000), efforts to develop effective control tools such as new antimalarials and blood stage- or liver stage vaccines have become increasingly critical (Richie and Saul, 2002; Ridley, 2002; World Health Organization, 2000). Another strategy is to block malarial transmission from gametocyte carriers to the vector mosquitoes by using a transmission-blocking vaccine (Carter et al., 2000; Kaslow, 1997) or a drug which interrupts parasite development in the mosquito vector (Butcher, 1997). The strategy of blocking malarial transmission has been promoted inter alia to limit the spread of malaria in areas of low endemicity, and to halt the emergence and spread of resistance to blood schizontocides (Coleman et al., 1994).

However, the number of compounds which have been confirmed to have transmission-blocking activity is quite limited (Butcher et al., 2000; Coleman et al., 1994; Coleman et al., 2001; Enosse et al., 2000). Most candidates evaluated do not qualify for further development because of problems with toxicity, cost of development, or other factors (Coleman et al., 2001). If currently approved drugs (for whatever purpose) are proven to posses malaria transmission-blocking activity, practical evaluation should be greatly accelerated and their impact fully exploited.

Isonicotinic acid hydrazide (INH), one of the front-line anti-tuberculosis drugs has been reported to inhibit the transmission of Plasmodium yoelii nigeriensis from infected mice to Anopheles stephensi mosquitoes by a totally unknown mechanism (Helmut, 1998). Shibata et al. (1996) reported that INH-treatment of rats decreased xanthurenic acid (XA) excretion into urine to undetectable levels by inhibiting kynurenine aminotransferase activity in the liver. We have previously reported that factors (which include XA) derived from both vertebrate host blood and the vector mosquito, regulate malarial gametogenesis in the mosquito gut (Arai et al., 2001). Taken together, we hypothesised that INH may inhibit gametogenesis by depleting host blood XA.

The objectives of the present study were, to examine: (i) on which developmental stage INH exerts its inhibitory effect, (ii) whether the inhibitory effect of INH is direct or indirect, and (iii) whether INH-treatment decreases gametocyte activating factor (GAF) activity of the blood.

Section snippets

Mosquitoes

The black-eyed (wild-type) strain of Aedes aegypti, originally from Bangkok, was obtained from Prof. H. Townsend (Liverpool School of Tropical Medicine, UK). The kh mutant of Ae. aegypti, originally described by Bhalla as the White Eye (WE) strain (Bhalla, 1968), was obtained from Dr. M. Benedict (CDC, Atlanta, GA). The SDA500 strain of An. stephensi was maintained at Imperial College. Mosquitoes were reared as previously described (Sinden, 1996).

Parasites

Plasmodium berghei ANKA strain, clone 2.34, was

Effect of INH on exflagellation and ookinete development in vitro

In the in vitro experiments, INH did not inhibit exflagellation and ookinete development of P. gallinaceum, and ookinete development of P. berghei, within range of tested concentrations, i.e., 10 nM to 10 mM, 1 μM to 1 mM, and 100 μM to 2 mM, respectively (data not shown).

Effect of INH-treatment on blood stage parasites and infected animals

At any dose used in this study, no significant effect of INH was observed on the course of parasitaemia and microgametocytaemia of either P. gallinaceum-infected chickens (Figs. 1A and B) or P. berghei-infected mice (Figs. 1D and E).

Discussion

We confirmed the earlier observation of Helmut (1998) that INH has a transmission-blocking effect on rodent malaria through the anopheline mosquito, and extended the observation to include P. gallinaceum in Ae. aegypti, in both models oocyst development was inhibited in a dose-dependent manner. However, concerning the nature of the analysis using pooled data which potentially suffers from variance in each experiment, caution should be taken for the interpretation of the dose–response curves.

Acknowledgments

This investigation received financial support from the UNDP/World Bank/WHO Special Programme for Research and Training in Tropical Diseases (TDR). The authors would also like to thank the Japan Society for the Promotion of Science (JSPS Postdoctoral Fellowships for Research Abroad 1999 to M.A.) for support.

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