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Key Words cell proliferation, antiapoptosis, invasion, endothelial cell, erythrocyte, type IV secretion system
Abstract The genus Bartonella comprises several important human pathogens that cause a wide range of clinical manifestations: cat-scratch disease, trench fever, Carrión's disease, bacteremia with fever, bacillary angiomatosis and peliosis, endocarditis, and neuroretinitis. Common features of bartonellae include transmission by blood-sucking arthropods and the specific interaction with endothelial cells and erythrocytes of their mammalian hosts. For each Bartonella species, the invasion and persistent intracellular colonization of erythrocytes are limited to a specific human or animal reservoir host. In contrast, endothelial cells are target host cells in probably all mammals, including humans. Bartonellae subvert multiple cellular functions of human endothelial cells, resulting in cell invasion, proinflammatory activation, suppression of apoptosis, and stimulation of proliferation, which may cumulate in vasoproliferative tumor growth. This review summarizes our understanding of Bartonella-host cell interactions and the molecular mechanisms of bacterial virulence and persistence. In addition, current controversies and unanswered questions in this area are highlighted.
INTRODUCTION
Bartonella bacilliformis has been known as a human pathogen for nearly one century (3), and it was the only species of the genus Bartonella until the beginning of the 1990s. Since then, the reclassification of previously described genera based on 16S rRNA sequences (i.e., Grahamella and Rochalimaea) (11, 13, 45, 95, 107, 121, 123) and the description of novel species isolated from various animal reservoirs (9, 10, 36, 44, 54, 55, 68-70, 79, 124) resulted in a major expansion of the genus Bartonella to currently 20 species, among which 8 have been associated with human disease (3, 31, 63, 68, 70, 91, 96, 121, 124) (Table 1). The human pathogenic species are extraordinarily adept at establishing long-term infections that can either manifest as acute or chronic disease, or be clinically asymptomatic with the potential to resurface later. Understanding the cellular interactions and factors that contribute to this long and complex relationship between pathogen and host is essential to our ability to modulate its clinical outcomes. In this review I discuss diseases caused by Bartonella species in the context of their host range, pathology, pathogen-host cell interaction, and pathogenesis. I highlight commonalities and differences that aid in the understanding of their pathogenic mechanisms, describe recent studies of Bartonella virulence factors that...