The High Incidence of Fatal Damage Rendered by T. Gondii Infection - Essay Example

? Protective immune response against Toxoplasma gondii elicited by recombinant DNA vaccines Introduction The high incidence or fatal damage rendered by T. gondii infection evidently indicates the urge for the development of a vaccine. The development of effective DNA vaccines against T. gondii can help mitigate and control the spread of toxoplasmosis, a move that is critical to both human health and the farming industry. Immunization with DNA vaccines can stimulate humoral and cell-mediated immune response, all of which are significant in conferring immunity to Toxoplasma gondii (Dubey 2008, p.467). Statistics indicate that, in the UK, close to 30% of humans are infected by the parasite, and as such, are a haven of dormant cysts within their brain; however, very few of the infected manifest explicit symptoms of disease. The increased incidence within certain European countries has largely been attributed to differentials in the mode of food preparation, especially with enhanced risk associated with eating undercooked meat. Atypical and/or recombinant strains of T. gondii are linked to considerable disease manifestations, inclusive of pulmonary involvement, ocular disease, and splenomegaly in several non-European countries. Neurological disease can manifest in these subjects in the event that they become immunosuppressed. It is evident that infection during pregnancy may lead to abortion or foetal infection (Pratt and Roberts 2009, p.122). T. gondii infections manifested in immunocompetent hosts predominantly remain asymptomatic or regularly trigger mild symptoms. Nevertheless, in immunocompromised subjects such as individuals with AIDS, organ transplant recipients, and malignancy patients, T. gondii infection can lead to severe or even fatal damage as an opportunistic parasite (Innes, Bartley, Maley, Katzer and Buxton 2009, p.346). Furthermore, congenital toxoplasmosis is of significant clinical importance since it occurs as severe maternal infection during pregnancy that affects the fetus, yielding retinochoroiditis, intracranial calcifications, mental retardation, hydrocephalus, and even cases of unprompted abortion and neonatal death (Pratt and Roberts 2009, p.123). Similarly, T. gondii infection in animals possesses considerable economic significance as it causes abortion, neonatal loss, and stillbirth, especially among sheep. The present T. gondii controls feature primarily on chemotherapy; however, the available drugs mainly possess many side effects along with challenges of reactivation (Guex-Crosier2009, p.140). This renders a vaccine against toxoplasmosis to be of high priority, although, currently there is no vaccine approved for human use. Toxovax sums up as the only commercial vaccine available for use in livestock and grounded in the live attenuated S48 strain (Petersen 2007, p.214). Nevertheless, live vaccine remains inadequately characterized at the genetic level and potentially caries the intrinsic of relapsing to virulence. This makes the development of an effective and safe vaccine against T. gondii in both humans and animals to be a realistic goal (Angus 2000, p.317). T. gondii manifests an intricate life cycle bearing three morphologically unique infectious stages. Each of the infectious stages detailing tachyzoites (speedily multiplying parasites of the severe phase of infection), bradyzoites (those engaged in tissue cycts), and sporozoites (those engaged in oocysts) bears a characteristic biological function to play. Moreover, accumulating evidences signify that vaccination with stage-specific antigens yields stage-limited protection (Jongert, Roberts, Gargano, Forster-Waldl and Petersen 2009, p.252). Thus, in the course of studying vaccines against T. gondii, it is critical to develop a multigenic vaccine that links with growth stages in diverse life cycle stages so as to overcome the deficiency of employing single antigen as a vaccine candidate. Multiple studies directed at developing recombinant vaccines against T. gondii have mainly spotlighted surface antigens (SAGs), rhoptry antigens (ROPs), dense granule antigens (GRAs), and microneme antigens (MICs). Among the multiple potential vaccine candidates of T. gondii, SAG1, the significant surface protein of tachyzoites remain perceived to be a capable vaccine candidate that can draw both humoral and cellular immune responses (Vercammen et al. 2000, p.38). As a result, a number of studies have been undertaken with purified SAG1, recombinant SAG1, or SAG1-derived peptides. Disease Disease outcome is predominantly dependent upon a number of factors such as host genetics status, mode of transmission, and parasite strain. T. gondii infection in the immune-competent host is mainly not perceived as a significant problem. Mild flu-like symptoms remain manifested at the beginning of infection that coincides with speedily dividing tachyzoite form for the parasite. Immunocompromised individuals such as individuals infected with HIV or immunosuppressive therapies that infected with T. gondii can manifest severe systematic, ocular, or predominantly neurological disease (Jones, Alexander and Roberts 2006, p.635). In the absence of a sufficient immune response, tachyzoites multiply unabated leading to tissue destruction that can be severe and even fatal. The inflammatory immune response stimulated by tachyzoites can lead to immune-mediated tissue destruction. Hence, a delicate balance between stimulating and averting immune response is critical for Toxoplasma to launch a chronic infection (Jones, Alexander and Roberts 2006, p.636). The success of Toxoplasma as a broad pathogen emanates from the simplicity by which it can be transferred vis-a-vis intermediate hosts. Once inside the host, the parasite devises powerful tools critical to modulating its host cell and establishing a chronic infection capable of evading the host’s immune system and all known anti-toxoplasmatic drugs. Immunological Lessons The immune response to T. gondii can be described as intricate and multifaceted. Immune responses amid young stages of T. gondii remain typified by macrophages and dendritic cells (DC). These cells remain mainly activated in mice after parasite internalization (the effect on humans is yet to be known). The organism possesses several pathogen-associated molecular patterns that interrelate with Toll-like receptors within the mammalian host to initiate a speedy immune response by innate immune cells such as macrophages and dendritic cells (Leyva, Herion and Saavedra 2000, p.71). IL-12 produced by the cells induces natural killer (NK) cells to yield IFN-Y, which, in turn, acts on infected cells to destroy parasites via the induction of reactive nitrogen intermediates, or restriction of their development via selective weakening of tryptophan that required by the parasite. Acquired immunity against T. ingodii develops afterwards, and remain typified by robust CD4+ and CD8+ T cell activity (Leyva, Herion and Saavedra 2000, p.70). The cytokine gamma interferon (IFN-Y) continues to be crucial in resistance to the parasite during the consecutive acute and chronic stages of infection, propelling the delineation of CD4+ T lymphocytes distinct for parasite antigens to a helper T cell type (Th1) cytokine profile. Most significantly, the freshly generated CD8+ T cells become critical to control parasite replication by serving as supplementary sources of IFN-Y, as well as establishing cytotoxic activity against infected cells. This eradicates parasite factories and subsequently prevents reactivation of infection. Genetic Vaccines: DNA Molecules and Live Vectors Early studies mainly employed killed or homogenized parasites, followed by crude extracts and then, enriched/purified parasite components. The rise of recombinant DNA technology enabled parasite proteins to be expressed and tested within experimental systems(Leyva, Herion and Saavedra 2000, p.71). The family of vaccine candidate antigens encompasses T. gondii membrane-associated surface antigen SAG1 (10, 18) and SAG2 (4); excreted-secreted dense-granule protein GRA1 (8, 9), GRA4, GRA6 (8), and GRA7 (3, 8, 9, 16); rhoptry proteins ROP1 (3, 10) and ROP2 (9, 18); and micronemal proteins MIC1, MIC2, MIC3 (14), and MIC6 (13), GRA proteins remain powerful antigens that activate strong T and B cell responses upon infection and GRA7 remain articulated by all infections stages of T. gondii (6, 8) (Zhou, et al. 2012, p.1802). ROP1 is released at the time of infection into the establishment of parasitophorous vacuole, and hinges on the T. gondii penetrating enhancing factor. Proteins are exceptional inducers of antibodies; however, they manifest some difficulties to induce significant levels of T lymphocytes. Genetic vaccines, on the other hand, are highly efficient to induce antigen-specific T lymphocytes (Hong, Guanjin, Haifeng and Huanqin 2001, p.317). This category of vaccines represents several technologies that incorporate direct delivery of genes encoding antigens of interest to host cells, which subsequently serve as antigens factories and immune-related processing plants (Khan, Ely, and Kasper1991, p.3501). In order to enhance the imunogenecity of DNA vaccines within large animal models, a number of methods have been employed including enhancements in the design of the plasmid and antigen presentation; delivering numerous antigens simultaneously; employing plasmid molecules as part of prime-boost immunization systems; and, employing chemical adjuvants or immunomodulatory molecules formulated into microparticles or liposomes rate (Khan, Ely, and Kasper1991, p.3502). Nevertheless, at present, the low immunogenicity of DNA vaccines has compelled researchers to spotlight alternative immunization vectors, and recombinant bacteria or viral vectors that carry and express DNA successions into the host organisms more efficiently, have steadily replaced bacteria plasmids for experimental vaccination studies. The Efficacy of DNA Vaccines The efficacy of genetic vaccination with a DNA encoding the T. gondii SAG1 (P30) surface antigen has been established in a number of studies. Mice immunized with a plasmid encoding SAG1 indicated 80-100% protection, which, in turn, enhanced the survival time of infected mice and minimized the count of brain cysts in mice. DNA vaccination can be employed widely and successfully to elicit humoral and cellular immune responses in diverse vertebrate host species. Such studies have evidently established that interferon gamma plays a principal role in controlling both acute and chronic phases of toxoplasmosis (Oran and Robinson 2003, p.1999). This stems from the fact that since the plasmid employed for DNA vaccine manifest to contain immunostimulatory sequences inclining to Th1, DNA vaccination of mice with appropriate antigens might stimulate protective immunity against toxoplasmosis. In the intervening time, the selection of the vaccine adjuvant is as critical as selection of the immunogen for adjuvant that may yield to an appropriate response. A number of immunology studies have demonstrated the potential function of Toxoplasma gondii antigens SAG1 and GRA 2 as vaccine candidates. This stems from the construction of recombinant DNA vaccines pVAX1-SAG1, pVAX1-GRA2, and pVAX1-SAG1-GRA2 termed as PSAG1, pGRA2, and pSAG1-GRA2 respectively (Oran and Robinson 2003, p.2000). In addition to being significant surface antigens of T. gondii, GRA sums up as a critical latent vaccine entrant for treating toxoplasmosis. This stems from the fact that GRA, when secreted in large quantity, doubles up as the major component of both the vacuole surrounding tachyzoite and the cyst wall surrounding slower-growing bradyzoite. Immunology responses to GRA2 may be critical in controlling infection since immunization with the native protein partly shields mice against acute toxoplasmosis. In one of the studies conducted by Meng et al., the Toxoplasma gondii protein demonstrated to be antigenic, as well as immunogenic and was a possible vaccine candidate against toxoplasmosis (2012, p.273). In this study, mice vaccinated with Psag1, p14-3-3, or psga1/14-3-3 established enhanced levels of igg2a and gamma interferon. This suggested a modulated immune type response Th1 (p Read More