Cardiac Failure in C5-Deficient A/J Mice afterCandida albicansInfection

Abstract

The effect of a deficiency in the C5 component of complement on the pathophyisology of infection with the fungal pathogen Candida albicans was studied by using the A/J inbred mouse strain and the BcA17 congenic mouse strain. Acute infection caused by intravenous injection of C. albicans blastospores is associated with rapid fungal replication in the heart, brain, and, in particular, kidneys of C5-deficient mice. Histological studies and analysis of markers for tissue damage indicated that the heart is the organ that is most affected and that it ultimately fails in C5-deficient mice. In A/J and BcA17 mice, tissue damage is associated with (i) cellular infiltration in the heart, which is not seen in the kidney despite the higher fungal load in the latter organ, and (ii) a very strong inflammatory response, including elevated levels of many cytokines and chemokines. This results in cardiomyopathy, which is associated with elevated levels of creatine kinase and cardiac troponin I in the circulation. Damage to the cardiac muscle is associated with metabolic changes, including hypoglycemia, decreased lipid utilization resulting in elevated levels of cardiac triglycerides, and unproductive glucose utilization linked to a dramatic increase in the level of pyruvate dehydrogenase kinase 4 (Pdk4), a negative regulator of the pyruvate dehydrogenase complex.Systemic infection with Candida albicans is a significant cause of morbidity in immunocompromised hosts, including transplant recipients and AIDS patients. The organs affected and the major sites of fungal replication during disseminated candidiasis are the kidney, heart, and brain, and death follows multiple-organ failure (24,30). The mouse model of acute infection with C. albicans is a valuable experimental model for studying microbial pathogenesis, as it includes many of the clinical features of the human condition (2, 46). In addition, a genetic approach with mice can be used to identify host genes and proteins that regulate the onset of, response to, and ultimate outcome of infection. We previously studied the differential susceptibility of inbred strains A/J and C57BL/6J (B6) to acute infection with C. albicans (29). The A/J mouse strain is exquisitely sensitive to candidiasis, and there are high fungal loads in target tissues and rapid death occurs within 24 h following intravenous injection of 3 ϫ 10 5 C. albicans blastospores. On the other hand, B6 mice survive up to 2 weeks following infection and ultimately die of kidney failure, a consequence of continued fungal replication at that site. Using the extent of replication in the kidney, brain, and heart, as well as the survival time, as phenotypic markers of susceptibility, we determined that the differential susceptibility of A/J and B6 mice to C. albicans infection segregates as a single gene effect in A/J ϫ B6 F2 mice which corresponds to a loss-of-function mutation in the C5 component of the complement pathway (45).C5 is a component of the complement pathway, and it plays several critical roles in the innate ...

Host response toCandida albicansbloodstream infection and sepsis

“…60a, 70,71 The prominent effects of C5 deletion are most likely related to the lack of its activation product C5a, which has been shown to be critical for activation of human monocytes by C. albicans and which significantly enhances the release of pro-inflammatory cytokines, e.g., IL-6 and IL-1b. 72 Figure 2.…”

Genetic Control of Susceptibility to Candida albicans in SM/J Mice

“…6C). Similarly, the hyper-susceptible A/J strain exhibits elevated levels of CCL2 following infection with C. albicans (16,67), prompting us to postulate that the effect of Carg5 on CCL2 serum levels, albeit highly correlated with fungal load, may be secondary and adaptive to a primary myeloid defect. Whether SM/J mice possess impaired emergency myelopoiesis remains to be ascertained, and it will entail challenging this strain with other pathogens.…”

Caracterização das bases moleculares da suscetibilidade imunológica à infecção por Candida albicans

“…Linhagens como A/J, DBA/2J e CBA/CaH mostraram elevada suscetibilidade a este patógeno, enquanto outras linhagens, como C57Bl/6 e BALB/c mostraram-se comparativamente mais resistentes (Ashman et al, 1996;Peltz et al, 2011;Tuite et al, 2004). Esse padrão de resistência e suscetibilidade pode ser observado por meio de modelos de infecção sistêmica, onde podem ser avaliados a colonização de órgãos específicos por células de C. albicans, carga fúngica nestes órgãos, avaliação de lesão, e principalmente prolongada sobrevivência nestes modelos (Ashman et al, 1996;Mullick et al, 2006). Vários fatores foram relacionados à suscetibilidade, tanto no modelo murino quanto em pacientes humanos.…”

“…Vários fatores foram relacionados à suscetibilidade, tanto no modelo murino quanto em pacientes humanos. Por exemplo, deficiências no sistema Complemento, um importante fator na resposta imune inata, implicam em suscetibilidade a C. albicans em modelos murinos (Mullick et al, 2006;Tsoni et al, 2009). Camundongos de linhagens suscetíveis apresentam, em geral, uma disregulação da resposta inflamatória, que resulta em elevado dano tecidual e consequente falha no funcionamento de órgãos e morte (Lionakis et al, 2011;Mullick et al, 2004;Mullick et al, 2006).…”

“…Por exemplo, deficiências no sistema Complemento, um importante fator na resposta imune inata, implicam em suscetibilidade a C. albicans em modelos murinos (Mullick et al, 2006;Tsoni et al, 2009). Camundongos de linhagens suscetíveis apresentam, em geral, uma disregulação da resposta inflamatória, que resulta em elevado dano tecidual e consequente falha no funcionamento de órgãos e morte (Lionakis et al, 2011;Mullick et al, 2004;Mullick et al, 2006). Além disso, polimorfismos em determinados genes, especialmente genes relativos à resposta imune, mostraram ser importantes tanto no modelo murino, quanto em pacientes humanos (Plantinga et al, 2012a;Radovanovic et al, 2011b;Smeekens et al, 2013).…”