br Oxidative microbe killing and V ATPase Oxidative killing

Oxidative microbe killing and V-ATPase Oxidative killing of phagocytosed microorganisms is predominately achieved through the uptake of large quantities of molecular oxygen by the infected cell and the activity particularly of the NADPH oxidase complex on phagosomes (Savina et al., 2006) and the plasma membrane. There are four NADPH oxidase isoforms, NOX1 through NOX4, and NOX2 is the most relevant here in that mutations in NOX2 can lead to chronic granulomatous disease which comes with increased sensitivity to infection (Pizzolla et al., 2012). Oxidative defense is based on the ‘oxidative burst‘ which is the flushing of the phagosome lumen and of the extracellular space with large quantities of reduced oxygen (O2− or superoxide anion). The superoxide anion has characteristics of an oxygen radical and may kill some microorganisms by itself although, due to its anion character, it cannot well permeate membrane bilayers. O2− can react with protons forming hydrogen peroxide which permeates membranes much faster and which has microbicidal properties. Therefore, acidification of phagosomes with H+ promotes hydrogen peroxide formation and consumption of luminal protons. This is the reason why phagosomes may actually turn slightly alkaline right after xpo 1 (Mantegazza et al., 2008). In parallel to the oxidative burst, nitrogen oxide may form in the phagosome, catalyzed by the nitric oxide synthase. Nitric oxide and superoxide derivatives may react with each other culminating in the production of strongly antimicrobial peroxynitrite (ONOO−) and H2O2 may react in the Fenton reaction forming hydroxyl radicals (summarized in Fig. 3). It should be noted that the extent of the oxidative burst reaction is regulated by the immune status of the producing cell and that the use of certain phagocytic receptors can stimulate the oxidative burst much more than others. For example, clustering of the immunoglobulin receptor (Fcγ receptor) causes the generation of high levels of radical oxygen species and crowding of the mannose receptor of low levels (Underhill and Ozinsky, 2002). In summary, V-ATPase supports oxidative killing by turning weakly microbicidal compounds into more effective ones.
How pathogenic microorganisms deal with compartment acidification
Conclusions On one hand, V-ATPase is a central protein complex in the killing and destruction of intracellular microorganisms whether they are pathogens or non-infectious microbes. On the other hand, virulence features of pathogens of the genera Coxiella, Leishmania, Salmonella and others are actually supported by V-ATPase activity. This clearly shows that a general up- or downregulation of V-ATPase cannot be the all-encompassing approach to combat infectious diseases. Rather, a strategy tailored to each pathogeńs needs and sensitivities is necessary when looking at new V-ATPase-targeted anti-infectives. Also, more comprehensive and controlled analyses into how precisely V-ATPase activities support or inhibit antimicrobial defenses, are necessary. Central questions are: Which aspects of acidification precisely (such as more hydrogen peroxide, increased hydrolase activities, more protons etc.) cooperate in eradication of a given microorganism? And which are the molecular and structural bases for the differences?
Funding Collaborative work on V-ATPase in the laboratories of AH and PS has been funded through a grant of the Deutsche Forschungsgemeinschaft (DFG) as a part of priority programme 1580 (SPP1580).
Acknowledgements
Introduction Testosterone plays important role in the development and function of the male reproductive tract. However, its role in the regulation of vas deferens fluid pH remains unknown. Vas deferens plays important role in transporting the sperm from the epididymis to the ejaculatory ducts with pH and electrolytes content of its fluid were precisely regulated. These regulation is crucial for sperm survival [1]. The pH of epididymal and vas deferens fluid is reported to be acidic [2]. Acidification of the luminal fluid pH in general is reported to involve the membrane transporter proteins including vacuolar (V)-ATPase [2,3]. The acidic pH of vas deferens fluid is necessary to maintain the sperm quiescence and to prevent premature activation of sperm’ acrosomal enzymes during their storage in cauda epididymis and vas deferens [4].