PMC:4503824 / 25253-28923 JSONTXT

{"project":"2_test","denotations":[{"id":"25498576-21472389-43267808","span":{"begin":622,"end":626},"obj":"21472389"},{"id":"25498576-12778493-43267809","span":{"begin":844,"end":848},"obj":"12778493"},{"id":"25498576-23216912-43267809","span":{"begin":844,"end":848},"obj":"23216912"},{"id":"25498576-12778493-43267810","span":{"begin":1001,"end":1005},"obj":"12778493"},{"id":"25498576-8621921-43267811","span":{"begin":1876,"end":1880},"obj":"8621921"},{"id":"25498576-21960987-43267812","span":{"begin":1978,"end":1982},"obj":"21960987"},{"id":"25498576-1639513-43267813","span":{"begin":2218,"end":2222},"obj":"1639513"},{"id":"25498576-11035733-43267814","span":{"begin":2328,"end":2332},"obj":"11035733"},{"id":"25498576-8757810-43267815","span":{"begin":2689,"end":2693},"obj":"8757810"},{"id":"25498576-9009313-43267816","span":{"begin":3155,"end":3159},"obj":"9009313"},{"id":"25498576-10515814-43267817","span":{"begin":3664,"end":3668},"obj":"10515814"}],"text":"8 Neutrophils\nNeutrophils, like macrophages and dendritic cells, capture and degrade pathogens and have a particular role in the initiation of inflammation, in response to infection. Thus, neutrophils may be expected to play an important role in cryptococcal clearance. However, there is little evidence suggesting that neutrophils are necessary for control of cryptococcosis as there is no association between diseases of the neutrophil (e.g. chronic granulomatous disease, neutropenia) alone being a predisposing factor for cryptococcosis, but only in conjunction with additional immune deficiency (e.g. (Hirai et al., 2011)). Mouse studies support this conclusion, as although neutrophils are able to phagocytose and degrade C. neoformans, after neutrophil depletion the fungal burden is not enhanced (Mednick et al., 2003; Wozniak et al., 2012). Furthermore, in mice depleted of neutrophils, survival was improved, possible through an up-regulation of both Th1 and Th2 cytokines (Mednick et al., 2003). As a Th1 profile is thought to be essential in cryptococcal clearance, the combined effect of both profiles may lead to improved cellular clearance with minimised host damage, perhaps because, in normal infection, neutrophilic responses may actually be detrimental in terms of organising a Th1 vs Th2 skew.\nDespite a potential key role in orchestrating the type of immune response, neutrophils are primarily active in their use of oxidative and non-oxidative mechanisms to combat and degrade microbes. Neutrophils release reactive oxidative species and their intermediates (hydroxyl and hypochlorite ions) on encountering cryptococci. However, C. neoformans is able to counteract this host defence, through production of mannitol, which acts as a scavenger for these reactive oxygen intermediates, thus reducing their potential for cellular damage (Chaturvedi et al., 1996). Similarly, melanised cryptococci are also resistant to this neutrophil attack (Qureshi et al., 2011). A non-oxidative host defence delivered by neutrophils is through production of proteins found within their other granule types. These proteins, for example defensins (that are not present in mouse neutrophils (Eisenhauer and Lehrer, 1992)) exert a degradative effect on cryptococcal cells, in addition to oxidative mechanisms (Mambula et al., 2000). These anti-cryptococcal defences highlight how neutrophils are able to combat and degrade invading cryptococci, despite fungal burden not being neutrophil dependant.\nNeutrophils are activated by contact with cryptococcal components, for example the dose dependent release of pro-inflammatory cytokines in response to cryptococcal capsule (Retini et al., 1996). This indicates a host mechanism that is capable of using the cryptococcal capsule to recognise infection and may lead to further neutrophil recruitment. Conversely, neutrophils are attracted to sites of infection, and CD18 is an adhesion molecule involved in this step. It is suggested that cryptococcal capsule molecules are able to bind and functionally inhibit CD18, leading to impaired attraction of neutrophils to the site of infection (Dong and Murphy, 1997). This may indicate that C. neoformans actually halts the recruitment of neutrophils, potentially to avoid the release of pro inflammatory cytokines.\nIndividuals with late stage HIV infection do not show differences in the number neutrophils but specific functional defects have been described. For example, reduced expression of CD88, a C5a receptor, results in a decrease in IL-8 expression in response to cryptococcal infection and a subsequently reduced inflammatory response (Monari and Casadevall, 1999)."}