Immunoglobulin A1 Protease, an Exoenzyme of Pathogenic Neisseriae, Is a Potent Inducer of Proinflammatory Cytokines

Abstract

A characteristic of human pathogenic Neisseriae is the production and secretion of an immunoglobulin (Ig)A1-specific serine protease (IgA1 protease) that cleaves preferentially human IgA1 and other target proteins. Here we show a novel function for native IgA1 protease, i.e., the induction of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and IL-8 from peripheral blood mononuclear cells. The capacity of IgA1 protease to elicit such cytokine responses in monocytes was enhanced in the presence of T lymphocytes. IgA1 protease did not induce the regulatory cytokine IL-10, which was, however, found in response to lipopolysaccharide and phytohemagglutinin. The immunomodulatory effects caused by IgA1 protease require a native form of the enzyme, and denaturation abolished cytokine induction. However, the proteolytic activity is not required for the cytokine induction by IgA1 protease. Our results indicate that IgA1 protease exhibits important immunostimulatory properties and may contribute substantially to the pathogenesis of neisserial infections by inducing large amounts of TNF-α and other proinflammatory cytokines. In particular, IgA1 protease may represent a key virulence determinant of bacterial meningitis.

Carcinoembryonic Antigen Family Receptor Specificity of Neisseria meningitidis Opa Variants Influences Adherence to and Invasion of Proinflammatory Cytokine-Activated Endothelial Cells

“…The authors suggested that the pathophysiological events induced by these elevated levels of TNF-␣ might be required for meningococcal pathogenicity. We have recently shown that neisserial immunoglobulin A1 protease is a potent inducer of TNF-␣ in peripheral blood mononuclear cells (25). Likewise, meningococcal lipopolysaccharide is known to stimulate proinflammatory responses.…”

Type V Protein Secretion Pathway: the Autotransporter Story

“…Lorenzen et al (302) studied the immunogenic and immunomodulatory properties of the neisserial IgA1 protease. They found that IgA1 protease acts like a modulin by stimulating the release of tumor necrosis factor alpha (TNF-␣), interleukin-1␤ (IL-1␤), IL-6, and IL-8 from peripheral blood mononuclear cells but not the regulatory cytokine IL-10.…”

Botulinum neurotoxins: Perspective on their existence and as polyproteins harboring viral proteases

“…In doing so did the structural (epitopes) alterations bring about in the protease domain the array of substrate specificities, or was it the other way around, i.e., as the different protease substrate specificities developed (possible impelling force/pressure mentioned above) through structural changes antigenic profiles also changed in the other two domains? This enigma appears apparent in the immunoglobulin A1 (IgA1) endopeptidases produced by a variety of human pathogens such as Neisseria gonorrhoeae, N. meningitidis, and Haemophilus influenzae (Lomholt et al, 1992;Lorenzen et al, 1999). They cleave with high specificity a single peptide bond in the hinge region of human IgA1 but not IgA2.…”