How a Specific Component of Host Innate Immunity Modulates Microbial Evolution Towards Pathogenicity?

Researchers can use bacteria in controlled experimental environments to study evolution in real time. In-fact many bacteria have knack to adapt to abiotic challenges under lab environments, however less is known about affect of biotic challenges on adaptive evolution in bacteria.

Escherichia coli are versatile pathogens and commensals. Since there is evidence in literature that some E. coli that are pathogenic evolved actually from commensal strains, hence this organism becomes ideal for studying commensal to pathogenic switch. Most of laymen consider E. coli as friendly commensal, however when gastrointestinal barrier is disrupted, this commensal turns into pathogenic form. The break away from primary immune barrier or innate system is a critical trait relevant in the acquirement of bacterial virulence.

Since macrophages are defensive in nature, they directly attack pathogenic bacteria and kill them by RNS or ROS and phagocytosis. However, many pathogens have evolved mechanisms to evade such capture processes of macrophages. Such mechanisms include adaptive processes like capsule and biofilm formation.

In this study, researchers allowed E. coli to evolve under selective pressure of macrophages and tried to analyze how quickly and by which mechanism commensal E. coli develops resistance to macrophages. Several combinations of investigational evolution, phenotypic characterization, genome sequencing and mathematical modeling were used to tackle how fast and through how many adaptive steps commensal E. coli can acquire this immune evading virulence trait.

Results from the study indicate that E. coli can evolve and adapt very fast to evade innate immune system. Such pathoadaptive process involves the accumulation of mutations caused by transposon insertions and increasing pathogenicity in vivo. Under selective pressure E. coli can evolve in less than 500 generations using mechanisms;

  1.  Single transposable element insertion into the E. coli yrfF gene promoter.
  2. Insertion of IS186 into an ATP-dependent serine protease encoding Lon gene promoter.

Moreover authors have obtained a mathematical model that illustrates the dynamics of pathoadaptive process where in clones carrying distinct beneficial mutations emerge rapidly and turn virulent.

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Reference: The Genetic Basis of Escherichia coli Pathoadaptation to Macrophages.

Migla Miskinyte, Ana Sousa, Ricardo S. Ramiro, Jorge A. Moura de Sousa, Jerzy Kotlinowski, Iris Caramalho, Sara Magalhães, Miguel P. Soares, Isabel Gordo. DOI: 10.1371/journal.ppat.1003802.

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Parasitic Infections and Mutilation of T-Cell Function

Recently a review has been published in PLOS Neglected Tropical Diseases (http://www.plosntds.org/). This review focuses mainly on the development of the four intracellular parasite species (Plasmodium spp., Trypanosoma cruzi, Toxoplasma gondii and Leishmania spp.) in the mammalian hosts they infect, with special emphasis on T lymphocyte function. These parasites after invading the host, blight T cell function and augment their apoptosis. Such impairments lead the host unresponsive for the parasite because of the collapse of the T cell number. This weakening of T-cells aids the parasites to survive throughout the infection or become persistent. All of such process follows a particular tier system as:

1: Invading/breaching the host barriers and integument or epidermis.

2: Down-regulate T cell function and lead to their exhaustion.

3: Apoptosis of T-cells or T-cell contraction.

4: Stay persistently in the host.

These parasites can accomplish apoptosis of host T-cells by activation-induced cell death (AICD) involving death ligands and caspase-8 or activated T cell autonomous death (ACAD) involving Bcl-2 family. This course of action respectively results in the formation of the death-inducing signalling complex (DISC) or apoptosome. Several studies have shown that patients infected with Plasmodium falciparum, Trypanosoma cruzi and Leishmania donovani have elevated levels of death ligand FasL. Also some studies have proven that engulfment of apoptotic cells stimulates expansion of parasites like Trypanosoma cruzi and Leishmania major inside host macrophages.

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This work is Licensed under Creative Commons Licenses.

Reference: Vasco Rodrigues,  Anabela Cordeiro-da-Silva, Mireille Laforge, Ali Ouaissi, Khadija Akharid, Ricardo Silvestre mail, Jérôme Estaquier mail.. DOI: 10.1371/journal.pntd.0002567

rK39-ICT Is Less Sensitive in Africa as Compared to Asia.

Leishmaniasis is a fatal systemic disease that occurs due to bite of Leishmania donovani carrier sandfly.  In Asia, Africa and Brazil Viseral Leishmaniasis is most prevalent and is caused by Leishmania donovani complex (L.infantum+L.donovani).

An immunochromatographic test, rK39 (an antibody based test) is used to detect the disease. This test is based on dual 39 amino acid repeats of a Sudanese L. donovani-obtained kinesin homologue of rK39, flanked by HASPB sequences.  However this test has less sensitivity in Africa than in Asia. Possible reasons for such variation could be:

  1. Molecular diversity that is continent specific
  2. Variable immunological response due to different IgG anti-Leish patient levels.

Immunoglobulin G or IgG titers were determined for VL patients from India and Sudan. It was found that IgG titers of VL patients from Sudan were less than Indian VL patients. About 46-61 folds higher mean ELISA titers were found for Indian VL patients as compared to Sudanese patients. Higher titers occurred in adults (both sexes) and children less than 16 years old. Possible cause for such lower titers could be Zinc deficiency or either variable antigencity. Malnutrition of zinc, iron and protein are known to trim down immune responses in experimental models.  Extensive research on zinc deficient models has established earlier that reduced B-cell responses and impairment of memory cells occurs. This could explain as why rK39-ICT has lower sensitivity in African areas or a lower titer of IgG.Picture1 Picture2

Since VL is not the only version of disease caused by Leishmania, other types like (post kala-azar dermal leishmaniasis) PKDL could be of curiosity. Assessment of PKDL patient antibody levels might be the future study of the authors. Such efforts could really speed up the process of disease detection in future and save many lives by earlier and easier diagnosis.

Reference:  Significantly Lower Anti-Leishmania IgG Responses in Sudanese versus Indian Visceral Leishmaniasis. Tapan Bhattacharyya, Duncan E. Bowes, Sayda El-Safi, Shyam Sundar, Andrew K. Falconar, Om Prakash Singh, Rajiv Kumar, Osman Ahmed, Marleen Boelaert, Michael A. Miles. (2014) DOI: 10.1371/journal.pntd.0002675