TGF-β in infections and infectious diseases

Leishmania is a genus of parasitic protozoa capable of causing a spectrum of human diseases. The GP46/M-2 membrane glycoprotein has been demonstrated in a murine model system to elicit a protective immune response against infection with Leishmania amazonensis; in highly susceptible BALB/c mice, immunization leads to significant protection against infection. In the present study, for induction of long-term immunological effects, two recombinant vaccinia viruses, derived from the wild type and attenuated variant 48-7 and expressing the GP46/M-2 protein, were constructed; to ensure safety, we used the attenuated vaccinia virus mutant (48-7) as a live vector. Susceptible BALB/c mice immunized with either GP46/M-2-recombinant vaccinia virus were significantly protected against infection with L. amazonensis; 45 to 76% of the animals were completely protected (sterile) against a challenge inoculum of 10(3) infective organisms. The protectively immunized animals demonstrated T- and B-cell-dependent immunological responses; both lymphokine responses as well as antibody responses and long-term memory are indicative of T-cell activation. This first report of the use of a recombinant vaccinia virus to induce protection against a Leishmania infection indicates that recombinant vaccinia viruses should be of value in the design of a safe and effective vaccine against this parasitic disease.

https://iai.asm.org/content/iai/61/8/3351.full.pdf

Recombinant vaccinia viruses expressing GP46/M-2 protect against Leishmania infection.

A prospective longitudinal survey of cutaneous leishmaniasis (Leishmania peruviana) was carried out in Peru on a study population of 4716 persons living in 38 villages (Departments of Lima, Ancash and Piura). Demographic and clinical data were collected from all individuals, and a Montenegro skin test (MST) was carried out on 72% (3418) of the study population. Each household was revisited at 3-monthly intervals for up to 2 years to detect new leishmaniasis cases; 497 people received a second MST at the end of the study. Analysis of the epidemiological data indicated that (i) 17% (16/94) of all infections were subclinical, (ii) this percentage increased significantly with age, (iii) clinical infections led to 73.9% protective immunity (95% C.I. 53.0-85.5%) and relatively permanent MST responsiveness (recovery rate = 0.0098/year; 95% C.I. 0.000-0.020/year), (iv) sub-clinical infections led to protective immunity, which was positively correlated with their MST induration size (increasing by 17.9% per mm; P < 0.0001), and a mean MST recovery rate of 0.114/year (4/421 man-months), and (v) recurrent leishmaniasis was dominated by reactivations, not by reinfections.

/pdf/cutaneous-leishmaniasis-in-the-peruvian-andes-an-1qigjgp7qu.pdf

Cutaneous leishmaniasis in the Peruvian Andes: an epidemiological study of infection and immunity

Visceral leishmaniasis has been targeted for elimination as a public health problem (less than 1 case per 10,000 people per year) in the Indian sub-continent by 2017. However, there is still a high degree of uncertainty about the natural history of the disease, in particular about the duration of asymptomatic infection and the proportion of asymptomatically infected individuals that develop clinical visceral leishmaniasis. Quantifying these aspects of the disease is key for guiding efforts to eliminate visceral leishmaniasis and maintaining elimination once it is reached. Data from a detailed epidemiological study in Bangladesh in 2002–2004 was analysed to estimate key epidemiological parameters. The role of diagnostics in determining the probability and rate of progression to clinical disease was estimated by fitting Cox proportional hazards models. A multi-state Markov model of the natural history of visceral leishmaniasis was fitted to the data to estimate the asymptomatic infection period and the proportion of asymptomatic individuals going on to develop clinical symptoms. At the time of the study, individuals were taking several months to be diagnosed with visceral leishmaniasis, leading to many opportunities for ongoing transmission. The probability of progression to clinical disease was strongly associated with initial seropositivity and even more strongly with seroconversion, with most clinical symptoms developing within a year. The estimated average durations of asymptomatic infection and symptomatic infection for our model of the natural history are 147 days (95 % CI 130–166) and 140 days (95 % CI 123–160), respectively, and are significantly longer than previously reported estimates. We estimate from the data that 14.7 % (95 % CI 12.6-20.0 %) of asymptomatic individuals develop clinical symptoms—a greater proportion than previously estimated. Extended periods of asymptomatic infection could be important for visceral leishmaniasis transmission, but this depends critically on the relative infectivity of asymptomatic and symptomatic individuals to sandflies. These estimates could be informed by similar analysis of other datasets. Our results highlight the importance of reducing times from onset of symptoms to diagnosis and treatment to reduce opportunities for transmission.

/pdf/quantification-of-the-natural-history-of-visceral-dd9bf60kzh.pdf

Quantification of the natural history of visceral leishmaniasis and consequences for control

Although traditionally mostly confined to the endemic areas of Latin America, Africa, the Middle East and Central Asia, cutaneous leishmaniasis is increasingly seen in clinical practices in the Northern hemisphere due to the consequences of tourism and armed conflict. It is a group of diseases with a varied spectrum of clinical manifestations, ranging from small, benign cutaneous nodules to disfiguring mucosal tissue destruction. Caused by several Leishmania spp., cutaneous leishmaniasis is transmitted to human beings and animals by sandflies. Clinical diagnosis is difficult because diseases of other etiologies with a similar clinical spectrum are common in endemic areas. Hence, any clinical suspicion of cutaneous leishmaniasis should be confirmed by parasitological diagnosis. The standard treatment of cutaneous leishmaniasis is still using pentavalent antimonials. Although effective, antimonials can have potentially severe side effects and, ideally, patients should be monitored closely while undergoing t...

W. Peters

Papers

The leishmaniases in biology and medicine. Volume II. Clinical aspects and control.