Thymic atrophy induced by Plasmodium berghei ANKA and Plasmodium yoelii 17XL infection.

The thymus is the anatomical site where T cells undergo a complex process of differentiation, proliferation, selection, and elimination of autorreactive cells which involves molecular signals in different intrathymic environment. However, the immunological functions of the thymus can be compromised upon exposure to different infections, affecting thymocyte populations. In this work, we investigated the impact of malaria parasites on the thymus by using C57BL/6 mice infected with Plasmodium berghei ANKA and Plasmodium yoelii 17XL; these lethal infection models represent the most severe complications, cerebral malaria, and anemia respectively. Data showed a reduction in the thymic weight and cellularity involving different T cell maturation stages, mainly CD4-CD8- and CD4+CD8+ thymocytes, as well as an increased presence of apoptotic cells, leading to significant thymic cortex reduction. Thymus atrophy showed no association with elevated serum cytokines levels, although increased glucocorticoid levels did. The severity of thymic damage in both models reached the same extend although it occurs at different stages of infection, showing that thymic atrophy does not depend on parasitemia level but on the specific host-parasite interaction.

Monocyte Locomotion Inhibitory Factor confers neuroprotection and prevents the development of murine cerebral malaria.

Cerebral malaria (CM) is a neurological complication derived from the Plasmodium falciparum infection in humans. The mechanisms involved in the disease progression are still not fully understood, but both the sequestration of infected red blood cells (iRBC) and leukocytes and an exacerbated host inflammatory immune response are significant factors. In this study, we investigated the effect of Monocyte Locomotion Inhibitory Factor (MLIF), an anti-inflammatory peptide, in a well-characterized murine model of CM. Our data showed that the administration of MLIF increased the survival and avoided the neurological signs of CM in Plasmodium berghei ANKA (PbA) infected C57BL/6 mice. MLIF administration down-regulated systemic inflammatory mediators such as IFN-γ, TNF-α, IL-6, CXCL2, and CCL2, as well as the in situ expression of TNF-α in the brain. In the same way, MLIF reduced the expression of CD31, CD36, CD54, and CD106 in the cerebral endothelium of infected animals and prevented the sequestration of iRBC and leucocytes in the brain microvasculature. Furthermore, MLIF inhibited the activation of astrocytes and microglia and preserved the integrity of the blood-brain barrier (BBB). In conclusion, our results demonstrated that the administration of MLIF increased survival and conferred neuroprotection by decreasing neuroinflammation in murine CM.

Use of mouse models to study the variability in virulence associated with specific genotypic lineages of Mycobacterium tuberculosis.

The host response against Mycobacterium tuberculosis show a wide spectrum of clinical manifestations in those patients who fail to control the infection. The course of the infection and its epidemiological consequences depend upon a complex interplay of host, environmental and bacterial factors. Experimental animal models have helped to define the influence of bacterial genetic diversity on virulence and on the immune response that is induced. For this purpose, experimental animals such as mice, guinea pigs and rabbits have been infected with selected clinical isolates obtained from outbreaks or from clinical epidemiology settings. Here we review the contribution of mouse models to defining the variability in virulence and immune response in relation to mycobacterial genetic diversity. Low dose aerosol infection in C57Bl mice or high dose intratracheal infection in BALB/c mice have demonstrated wide variability in virulence and immune responses induced by different bacterial genotypes, and each genotype has different phenotypes, with high and low virulence variants. In general, these studies have shown that high prevalent strains from big clusters are more virulent than low prevalent sporadic clinical isolates, and highly virulent strains induce non-protective immune responses with some correlation with clinical-epidemiological data. In the future selected strains from these types of studies should be analyzed with molecular technologies. These kinds of study will contribute to the identification of mycobacterial genes associated with virulence and immunogenicity.

Effect of polymerized-type I collagen in knee osteoarthritis. I. In vitro study.

BACKGROUND: Polymerized-type I collagen (polymerized-collagen) is a down-regulator of inflammation and a tissue regenerator biodrug. The aim of this study was to evaluate its effect in co-cultures of cartilage and synovial tissue from patients with knee osteoarthritis (OA). MATERIALS AND METHODS: Cartilage and synovial tissue from five patients with OA were co-cultured for 7 days in the presence or absence of 1% polymerized-collagen. To determine proteoglycans content, tissues were stained with alcian blue technique. Pro- and anti-inflammatory cytokines [interleukin (IL)-1beta, IL-8, IL-10, IL-12, tumour necrosis factor (TNF)-alpha, and interferon (IFN)-gamma] and tissue inhibitor of metalloproteinase (TIMP)-1 were measured in supernatants by ELISA and results were normalized by total protein concentration. Cartilage oligomeric matrix protein (COMP), type II collagen, TNF-alpha, IL-10 and Ki-67 expression were determined by immunohistochemistry. RESULTS: Polymerized-type I collagen induced an increase of 3- to 6fold cell proliferation (Ki-67), proteoglycans content, and COMP and type II collagen expression, whereas it inhibited IL-1beta and TNF-alpha production. IL-10 levels were up-regulated in treated vs. untreated cultures. No differences were found on IL-8 or TIMP-1 levels in supernatants from polymerized-collagen-treated co-cultures when compared with untreated cultures. IL-12 and IFN-gamma were undetectable. CONCLUSION: The addition of polymerized-type I collagen to cartilage and synovial tissue co-cultures induced up-regulation of chondrocytes proliferation and cartilage extracellular matrix proteins production (COMP, type II collagen and proteoglycans) as well as an anti-inflammatory cytokine (IL-10) and the down-modulation of pro-inflammatory cytokines (IL-1beta and TNF-alpha). It is possible that this mechanism might contribute to induce tissue regeneration and down-regulation of inflammation in OA.