Michael M Gicheru

Kenyatta University, Nairoba, Nairobi Area, Kenya

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Publications (22)17.58 Total impact

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    ABSTRACT: Our current understanding of the host immune response during leishmaniases largely derives from studies performed in mice due to the intrusive techniques required to study infected human patients. Swiss mice are highly resistance to Leishmania infections in concordance with observed response in humans while BALB/c mice indicate a high susceptibility phenotype. Developing a cross-breed between BALB/c and Swiss mice may have important consequences on disease development, immune responses and parasite killing, as yet, response of the cross-breed to Leishmania infection is superficial. The aim of the present study was to determine disease course and immune responses in F1 cross-breed between BALB/c and Swiss albino mice infected with L. major. Three mice groups were infected intradermaly with stationary phase L. major parasites with parental strains (BALB/c and Swiss albino) as controls. Lesion development was monitored weekly for 8 weeks and Monocyte chemotactic protein (MCP-1), Macrophage inflammatory protein (MIP-1α), Interferon gamma (IFN-γ) and IgG antibody quantified by enzyme-linked Immunosorbent assay. The data was analyzed using one-way analysis of variance and Tukey's-Kramer test. Results indicated F1 mice having intermediate lesion sizes, type 1 cytokine levels and footpad parasite loads as compared to the parental strains. However the F1 mice had low levels of IgG antibodies and parasite burden in the spleen. (P < 0.05). This study concludes that the F1 cross-breed between resistant and susceptible mice may be used as a requisite model to study the role of genetics in Leishmaniases and perhaps other intracellular parasites. This article is protected by copyright. All rights reserved.
    Scandinavian Journal of Immunology 02/2014; · 2.20 Impact Factor
  • International Journal of Morphology. 12/2013; 31(4):1322-1327.
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    ABSTRACT: Although there is currently no vaccine against leishmaniasis in routine use anywhere in the world, cases of self cure in cutaneous leishmaniasis, accompanied by solid immunity to reinfection, make vaccine development a feasible control method. Immunity against visceral leishmaniasis is mediated by IFN-γ-inducing parasite specific CD4+ and CD8+ T cells. We assessed the capacity of Leishmania donovani sonicate antigen delivered with alum-BCG (AlBCG), monophosphoryl lipid A (MPL) or montanide ISA 720 (MISA) to induce parasite specific CD4+ and CD8+ T cells involved in IFN-γ production following immunization of groups of the vervet monkey model of visceral leishmaniasis. Groups of vervet monkeys were immunized intradermally at three time points on days 0, 28 and 42 and T cell populations involved in the production of IFN-γ measured 21 days after final immunization. Significantly higher CD4+ T cells were induced in the group immunized with MISA+Ag compared to the AlBCG+Ag immunized animals (P<0.01) with both groups inducing significantly more CD4+ T cells than other groups (P<0.0001). Levels of CD8+ T cells were comparable between AlBCG+Ag and MISA+Ag groups, being significantly higher compared to the MPL+Ag group (P<0.001). The CD4+ T cells significantly correlated positively with CD8+ T cells in the studied groups (r=1.00; P=0.0167). We conclude that, immunization with MISA+Ag induces robust CD4+ as well as CD8+ T cells involved in the production of IFN-γ indicating stronger ability of this adjuvant over AlBCG in directing cellular immune response in the vervet monkey model. Keywords: Immunization; Adjuvants; CD4+ Th1 and CD8+ T cells; Th1 immune response; Visceral leishmaniasis; Vervet monkey model.
    scientia parasitologica. 03/2013; 14(1):7-9.
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    ABSTRACT: Leishmaniasis is a disease that ranges in severity from skin lesions to serious disfigurement and fatal systemic infection. Resistance to infection is associated with a T-helper-1 immune response that activates macrophages to kill the intracellular parasite in a nitric oxide-dependent manner. Conversely, disease progression is generally associated with a T-helper-2 response that activates humoral immunity. Current control is based on chemotherapeutic treatments which are expensive, toxic and associated with high relapse and resistance rates. Vaccination remains the best hope for control of all forms of the disease, and the development of a safe, effective and affordable antileishmanial vaccine is a critical global public-health priority. Extensive evidence from studies in animal models indicates that solid protection can be achieved by immunization with defined subunit vaccines or live-attenuated strains of Leishmania. However, to date, no vaccine is available despite substantial efforts by many laboratories. Major impediments in Leishmania vaccine development include: lack of adequate funding from national and international agencies, problems related to the translation of data from animal models to human disease, and the transition from the laboratory to the field. Furthermore, a thorough understanding of protective immune responses and generation and maintenance of the immunological memory, an important but least-studied aspect of antiparasitic vaccine development, during Leishmania infection is needed. This review focuses on the progress of the search for an effective vaccine against human and canine leishmaniasis.
    Journal of biomedical research. 03/2013; 27(2):85-102.
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    J M Mutiso, J C Macharia, M M Gicheru
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    ABSTRACT: The availability of hundreds of adjuvants has prompted a need for identifying rational standards for the selection of adjuvant formulation based on sound immunological principles for human vaccines. As cytokines elaborated by activated T cells are required for the regulation of isotype switch during B-cell development, a study of Th2 cytokines and subclass distribution of the antibodies may shed new light on the processes involved in the polarization of the immune responses during vaccination studies. The aim of this study was to identify an appropriate Leishmania vaccine adjuvant based on low Th2 cytokine and high value IgG2 antibody responses. Groups of vervet monkeys were immunized with Leishmania donovani sonicate antigen (Ag) alone or in conjunction with alum-BCG (AlBCG), monophosphoryl lipid A (MPL) or montanide ISA 720 (MISA) as adjuvants. Following three time point intradermal injections on days 0, 28 and 42, IL-4, IL-10 and IgG antibody subclasses were quantified by enzyme-linked immunosorbent assay (ELISA) and data analysed by one-way analysis of variance, Tukey-Kramer test and Spearman's rank correlation analysis. Results indicated relatively higher IL-4 and IL-10 cytokine responses following MPL + Ag as compared to AlBCG + Ag or MISA + Ag immunization. There was a positive significant correlation between IL-4 and IL-10 levels (r = 1.000; P = 0.0167). Significantly higher IgG2 antibody responses were associated with either AlBCG + Ag or MISA + Ag as compared to MPL + Ag immunization (P < 0.05). The study concludes that both AlBCG and MISA may be used in Leishmania vaccine studies that favour low Th2 cytokine and strong IgG2 antibody responses.
    Scandinavian Journal of Immunology 08/2012; 76(5):471-7. · 2.20 Impact Factor
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    ABSTRACT: In this study, we report on the safety and skin delayed-type hypersensitivity (DTH), responses of the Leishmania donovani whole cell sonicate antigen delivered in conjunction with alum-BCG (AlBCG), Montanide ISA 720 (MISA) or Monophosphoryl lipid A (MPLA) in groups of vervet monkeys. Following three intradermal injections of the inoculums on days 0, 28 and 42, safety and DTH responses were assessed. Preliminary tumor necrosis factor alpha (TNF-α) and interferon gamma (IFN-γ) levels were also measured and these were compared with DTH. Only those animals immunized with alum-BCG reacted adversely to the inoculum by producing ulcerative erythematous skin indurations. Non-parametric analysis of variance followed by a post-test showed significantly higher DTH responses in the MISA+Ag group compared with other immunized groups (p < 0.001). The MPLA+Ag group indicated significantly lower DTH responses to the sonicate antigen compared with the AlBCG+Ag group. There was a significant correlation between the DTH and cytokine responses (p < 0.0001). Based on this study we conclude that Leishmania donovani sonicate antigen containing MISA 720 is safe and is associated with a strong DTH reaction following immunization.
    Revista do Instituto de Medicina Tropical de São Paulo 02/2012; 54(1):37-41. · 0.96 Impact Factor
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    ABSTRACT: In a previous immunogenicity and efficacy study in mice, montanide ISA 720 (MISA) was indicated to be a better adjuvant than bacillus calmette guerin vaccine (BCG) for a Leishmania vaccine. In the present study, we report the safety, immunogenicity and efficacy of Leishmania donovani (L. donovani) sonicated antigen delivered with alum-BCG (AlBCG), MISA or monophosphoryl lipid A (MPLA) in vervet monkeys following intradermal inoculums. Vaccinated and control animals were challenged with virulent L. donovani parasites and the parasitic burden was determined. Only animals vaccinated with alum-BCG adversely reacted to the inoculum by producing ulcerative erythematous skin indurations. Non-parametric ANOVA followed by a post test showed significantly higher IgG antibodies, and revealed the presence of lymphoproliferative and interferon gamma responses in both AlBCG+Ag and MISA+Ag as compared to the MPLA+Ag or other groups (P < 0.001). We conclude that L. donovani sonicated antigen containing MISA is safe and is associated with protective immune response against Leishmania donovani infection in the vervet monkey model.
    Journal of biomedical research. 01/2012; 26(1):8-16.
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    ABSTRACT: Unhygienic practices have been associated with the spread of parasitic and bacterial infections in rural areas. This study was designed to verify the link between the frequencies of malaria and typhoid fever with selected rural practices in Njoro District, Kenya. A cross-sectional study involving observations, questionnaires and interviews was conducted to determine the socio-economic variables and practices/lifestyles in 336 randomly selected homesteads. Frequencies of malaria and typhoid fever in two randomly selected health centers were determined through a retrospective study for the period from 2004 to 2009. The respondents had large families (68%), low education level (67%) and high responsibility burden (67%). Individuals who did not boil drinking water constituted 61%. Boiling drinking water was less common among the poor, Odds Ratio (OR) of 2.36, χ(2) = 9.88, 95% Confidence Interval (CI) of 1.38-4.03. Respondents who washed their hands in a basin after using the latrines comprised 79.8% while 4.8% did not. 18.5% of the respondents did not use a soap to wash their hands after using the latrine. One third (33.6%) of the homesteads had dirty and inappropriate pit latrines while 2.7% of the homesteads lacked latrines. Failure to use mosquito bed nets was more likely to occur among the poor respondents, OR of 1.44, χ(2) = 1.74, 95% CI of 0.84-2.48. The frequencies of malaria and typhoid fever were an average of 29 and 24% respectively. Malaria and typhoid fever cases were relatively frequent due to adoption of inappropriate lifestyles and practices that predisposed the residents to infectious agents. Poverty seemed to play a significant role in the spread of malaria and typhoid fever.
    Journal of Community Health 07/2011; 37(1):224-33. · 1.28 Impact Factor
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    ABSTRACT: The in vitro and in vivo activity of diminazene (Dim), artesunate (Art) and combination of Dim and Art (Dim-Art) against Leishmania donovani was compared to reference drug; amphotericin B. IC50 of Dim-Art was found to be 2.28 ± 0.24 µg/mL while those of Dim and Art were 9.16 ± 0.3 µg/mL and 4.64 ± 0.48 µg/mL respectively. The IC50 for Amphot B was 0.16 ± 0.32 µg/mL against stationary-phase promastigotes. In vivo evaluation in the L. donovani BALB/c mice model indicated that treatments with the combined drug therapy at doses of 12.5 mg/kg for 28 consecutive days significantly (p < 0.001) reduced parasite burden in the spleen as compared to the single drug treatments given at the same dosages. Although parasite burden was slightly lower (p < 0.05) in the Amphot B group than in the Dim-Art treatment group, the present study demonstrates the positive advantage and the potential use of the combined therapy of Dim-Art over the constituent drugs, Dim or Art when used alone. Further evaluation is recommended to determine the most efficacious combination ratio of the two compounds.
    Revista do Instituto de Medicina Tropical de São Paulo 06/2011; 53(3):129-32. · 0.96 Impact Factor
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    International Journal of Morphology 06/2011; 29(2):353-362. · 0.21 Impact Factor
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    ABSTRACT: This work reports the anti-plasmodial activities of Warburgia ugandensis and Zanthoxylum usambarense commonly used as phytomedicines against malaria by some Kenyan communities. To determine the anti-plasmodial activities of extracts from Warburgia ugandensis and Zanthoxylum usambarense against Plasmodium knowlesi and Plasmodium berghei. Eight plant extracts were screened for in vitro anti-plasmodial activity against Plasmodium knowlesi, in a 96-well plate incubated at 37 degrees C on a RPMI culture medium supplemented with baboon serum. Of the eight, three were investigated for prophylactic and curative activities in BALB/c mice against drug-sensitive Plasmodium berghei in a 4-day test at a dose rate of 200mg/kg/day. Inhibitory concentrations (IC(50)) values of between 3.14 and 75 microg/ml, up to 69% chemosuppression of parasites growth and over 80% survivorship of treated mice were observed. The two medicinal plants, Warburgia ugandensis and Zanthoxylum usambarense possess bioactive compounds against malaria parasites and could be exploited for further development into malaria therapy.
    Journal of ethnopharmacology 04/2010; 130(1):158-62. · 2.32 Impact Factor
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    Joshua M Mutiso, John C Macharia, Michael M Gicheru
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    ABSTRACT: Over the last decade, there has been a flurry of research on adjuvants for vaccines, and several novel adjuvants are now licensed products or in late stage clinical development. The success of adjuvants in enhancing the immune response to antigens has led many researchers to re-focus their vaccine development programs. Although several vaccine candidates have been tested against leishmaniasis, there is yet no effective vaccine against this parasitic disease. Recent research has documented that efforts to develop effective Leishmania vaccine have been limited due to lack of an appropriate adjuvant. In view of this, this review paper outlines some of the adjuvants that have been used in Leishmania vaccine candidates and cites a few of the responses obtained from these studies. The aim of the present review is to consolidate these findings to facilitate the application of these adjuvants in general and experimental vaccinology.
    Journal of biomedical research. 01/2010; 24(1):16-25.
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    ABSTRACT: Immunity to the bovine apicomplexan parasite Theileria parva is associated with MHC-I restricted CD8+ T cell responses directed against the intralymphocytic schizont stage of the parasite. A number of schizont-stage antigens that are targets of CD8+ T cell responses from immune animals have been identified but an effective delivery strategy that consistently induces protective CD8+ T cell responses remains to be developed. This study aimed to determine whether fusing Tat, a cell penetrating peptide (CPP) from HIV-1 TAT, to a CD8+ T cell target antigen from T. parva (Tp2) enhances the cytosolic delivery and subsequent stimulation of bovine CD8+ T cell responses in vitro. Using IFN-gamma ELISpot and cytotoxicity assays, it was demonstrated that recombinant Tat-Tp2 fusion protein possessed a superior ability to access MHC-I processing and presentation pathway and to stimulate CD8+ T cell responses compared to recombinant Tp2 protein. Exposure of APC to Tat-Tp2 protein for only 30 min was sufficient for protein uptake and stimulation of CD8+ T cells. This work describes for the first time the utility of a CPP to enhance MHC-I presentation in a veterinary species and supports the evaluation of CPP fusion proteins in the induction of CD8+ T cell responses in vivo.
    Veterinary Immunology and Immunopathology 03/2009; 130(1-2):107-13. · 1.88 Impact Factor
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    ABSTRACT: Leishmaniasis, one of the highly neglected diseases is currently a significant health problem in northern Africa with a rising concern in western Africa because of co-infection with the Human Immunodeficiency Virus (HIV). In this review, we present a summarized analysis of the epidemiology, infective species, parasites reservoirs, diagnosis, treatment and control measures of leishmaniasis in northern and western Africa region. In northern Africa, the disease is prevalent in Morocco, Algeria, Tunisia, Egypt and Libya. Comparatively, there are low prevalence rates of the disease in West African countries including Cameroon, Ghana, Burkina Faso, Niger, Mali, Nigeria and Senegal. In North Africa, visceral leishmaniasis (VL) is caused by L. infantum and transmitted by Phlebotomus perniciosus and P. longicuspis. On the other hand, cutaneous leishmaniasis (CL) is mainly caused by L. major and transmitted by P. papatasi, P. duboscqi and P. pedifer with L. infantum and L. tropica causing lower incidences of the disease. Notably, Algeria is one of the countries that constitute 90% of CL cases worldwide. In Western Africa; CL is caused by L. major while VL is caused by L. donovani. In these regions, zoonotic and anthroponotic cutaneous and visceral leishmaniasis is a health problem that should be addressed urgently.
    African Journal of Infectious Diseases 01/2009; 3(1-ISSN: 2006-0165©2009):14-25.
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    ABSTRACT: ObjectiveTo determine the adjuvant potential of artemisinin with a soluble leishmanial antigen in vaccinating BALB/c mice.MethodsSeventy two female BALB/c mice were randomly assigned into six groups. The mice were vaccinated with soluble leishmania antigens (SLA) alone, artemisinin co-administered with SLA, SLA and Bacille Calmette Guérin (BCG) vaccine, and artemisinin and BCG alone. Unvaccinated mice formed the control group. The induction of cell-mediated immunity following vaccination was determined by measuring in vitro lymphocyte proliferation and the production of interleukin (IL)-4, IL-5 and gamma interferon (IFN-γ) determined by flow cytometry. Protection against L. major was determined by quantifying parasite burdens in L. major infected footpads using a limiting dilution assay and by measuring lesion sizes of the infected footpad compared to the contralateral uninfected footpad.ResultsMice receiving SLA plus artemisinin produced significantly high levels of IL-4 and IL-5 (P < 0.05) and low levels of IFN-γ, resulting in exacerbated disease. In addition, subcutaneous administration of SLA + artemisinin, artemisinin alone or SLA alone resulted in the development of large footpad swellings and high parasite loads that were comparable to those of the control unvaccinated mice (P > 0.05), resulting in exacerbated disease.ConclusionThese data suggest that artemisinin is not a suitable adjuvant for Leishmania vaccines. However, since artemisinin has been shown to be effective against Leishmania parasites in vitro and in vivo, further studies ought to be conducted to determine its immunochemotherapeutic potential when co-administered with Leishmania antigens.
    Journal of Nanjing Medical University. 01/2009;
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    ABSTRACT: The aim of this study was to evaluate the immunogenicity and efficacy of Montanide ISA 720 against BCG and alum as an adjuvant for Leishmania killed vaccine in BALB/c mice. Groups of mice were immunized with either, Baccile Calmette Guerin (BCG), aluminium hydroxide (alum) or Montanide ISA 720 (MISA) with killed Leishmania major (KLM) promastigotes antigen and later, sacrificed or challenged with virulent promastigotes. Vaccination with alum-KLM and BCG-KLM produced higher IgG responses than vaccination with Montanide ISA-KLM. Significantly higher lymphoproliferative response was obtained for the MISA-KLM mice than in both the alum-KLM and BCG-KLM vaccinated mice. The BCG-KLM group produced the highest interferon gamma (IFN-γ) while the alum-KLM gave the least IFN-g responses. Among the three adjuvants, BCG vaccination recorded the biggest lesion sizes, an indication of adverse reaction by BCG while the MISA 720 vaccinated mice showed the smallest cutaneous lesions. There was a good correlation between parasite burden and IFN-g level indicating IFN-g response as a sensitive parameter of immune response to the vaccine antigen used. The findings suggest MISA-KLM as a safe and effective immunization against cutaneous leishmaniasis but suggests for confirmation of the results in non-human primate model before clinical trials in humans.
    International Journal of Integrative Biology 01/2009;
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    ABSTRACT: This study characterises enterotoxin genes including nheA, nheB, nheC, hblA, hblC, hblD, entFM,cytK, bceT, and ess in 51 Bacillus cereus (B. cereus) strains isolated from pasteurized milk, processed cheese and cooked rice. A colony multiplex polymerase chain reaction was used to test for presence of genes in B. cereus isolates. Of the fifty one B. cereus isolates, 12 (33.3%) were from milk, 8 (22.2%) from cheese and 31 (60.7%) from rice. The isolates were classified into 15 toxigenic groups A - O according to the genes they contained. Group G had the highest number of strains, 8(15.7%) while groups D and H had one isolate each. The emetic toxin gene sequence (ess) was found in 18% while bceT was found in 20% of rice isolates. The cytK gene was present in 4% of milk and 8% of rice isolates. The cytK gene was not found in any of the cheese isolates. All the other genes were found in isolates from all the three food types. The toxigenic profiles of isolates from milk and cheese differed from those of rice isolates, indicating different food preferences among B. cereus strains.
    International Journal of Integrative Biology. 01/2009;
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    ABSTRACT: Objective This study compared the performance of the immunochromatographic strip (ICS) to the Venereal Disease Research Laboratory (VDRL) test and Treponema pallidum haemagglutination assay (TPHA) at a primary health care setting.
    Journal of Nanjing Medical University 01/2009; 23(5):317-321.
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    ABSTRACT: In Kenya, Leishmania major is responsible for human cutaneous leishmaniasis (CL). Natural infection with L. major of a vervet monkey and experimental susceptibility of some nonhuman primates (NHPs) from Kenya has been established. However, there has been no comprehensive study of the prevalence of zoonotic CL in Kenya. And also, no investigation has been done to assess whether NHPs could be potential reservoir hosts of L. major even when the involvement of reservoir animals is obligatory in transmission of this parasite. To achieve this, wild caught Chlorocebus aethiops (Vervet monkeys n=213), Papio cynocephalus anubis (olive baboons n=101) and Cercopithecus mitis (Syke's monkeys n=64) from five geographical locations in Kenya were screened for antibodies against L. major using enzyme linked immunosorbent assay (ELISA) and Western blot (WB) analysis. From the population of C. aethiops (n=213) captured, 57 were used in lymphocyte proliferation assay. ELISA revealed a high prevalence of leishmaniasis sero conversion in olive baboons 78/101 (77.2%), vervet monkeys 129/213 (60.6%) and Sykes' monkeys 43/64 (67.2%). WB detected anti-L. major antibodies in 48.5% (49/101) of the baboons, 48% (102/213) of vervet monkeys and 37.5% (24/64) of Sykes' monkey sera. Specific proliferation of peripheral blood mononuclear cells to L. major antigen was demonstrated in 17 of the 57 (29.8%) vervet monkeys. In conclusion, the results of serological assays provide strong circumstantial evidence that CL is prevalent in five Provinces of Kenya and that Kenyan NHPs could be could be a potential reservoir hosts of L. major.
    Acta tropica 11/2008; 109(2):136-40. · 2.79 Impact Factor
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    Jackson N Ombui, J Nduhiu Gitahi, Michael M Gicheru
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    ABSTRACT: No Abstract
    International Journal of Integrative Biology. 01/2008;