Lack of group X secreted phospholipase A2 increases survival following pandemic H1N1 influenza infection

Kelvin, Alyson A.; Dégousée, Norbert; Banner, David W.; Stefanski, Eva; Leόn, Alberto J.; Angoulvant, Denis; Paquette, Stéphane G.; Huang, Stephen S. H.; Danesh, Ali; Robbins, Clinton S.; Noyan, Hossein; Husain, Mansoor; Lambeau, Gérard; Gelb, Michael H.; Kelvin, David J.; Rubin, Barry B.

doi:10.1016/j.virol.2014.01.030

Cited by 22 publications

(18 citation statements)

References 72 publications

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“…Along with a more severe clinical profile, aged ferrets had an attenuated peripheral humoral and T cell immune response compared to adults and previously modeled immune responses following influenza infection (Cheng et al, 2013; Huang et al, 2011; Jang et al, 2013; Kelvin et al, 2014; O'Donnell et al, 2012; Paquette et al, 2014). We found aged ferrets to have a significant decrease in sustained HA antibody production following 1° and continued into secondary 2° pandemic H1N1 infection which may indicate a factor in the increased susceptibility to sequential influenza infections in the elderly.…”

Section: Discussionmentioning

confidence: 73%

Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

et al. 2014

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The major burden of influenza morbidity resides within the elderly population. The challenge managing influenza-associated illness in the elderly is the decline of immune function, where mechanisms leading to immunological senescence have not been elucidated. To better represent the immune environment, we investigated clinical morbidity and immune function during sequential homologous and heterologous H1N1 influenza infection in an aged ferret model. Our findings demonstrated experimentally that aged ferrets had significant morbidity during monosubtypic heterologous 2° challenge with significant weight loss and respiratory symptoms. Furthermore, increased clinical morbidity was associated with slower and shorter hemagglutinin antibody generation and attenuated type 1 T-cell gene responses in peripheral blood. These results revealed dampened immune activation during sequential influenza infection in aged ferrets. With the presence of an aged model, dissecting clinical morbidity, viral dynamics and immune response during influenza infection will aid the development of future prophylactics such as age specific influenza vaccines.

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Section: Discussionmentioning

confidence: 73%

Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

et al. 2014

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“…In addition, PLA2G10 is induced during in vitro differentiation of airway epithelial cells, from which it appears to elicit AA release directly (Hallstrand et al, 2013). Pla2g10 À/À mice are also partially protected from the early phase of lung inflammation following influenza infection (Kelvin et al, 2014). Moreover, PLA2G10 is a major sPLA 2 isoform detected in the airway of patients with asthma (Hallstrand et al, 2011).…”

Section: Asthma and Airway Inflammationmentioning

confidence: 99%

The Roles of the Secreted Phospholipase A2 Gene Family in Immunology

Murakami

Yamamoto

Miki

et al. 2016

Advances in Immunology

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Within the phospholipase A (PLA) family that hydrolyzes phospholipids to yield fatty acids and lysophospholipids, secreted PLA (sPLA) enzymes comprise the largest group containing 11 isoforms in mammals. Individual sPLAs exhibit unique tissue or cellular distributions and enzymatic properties, suggesting their distinct biological roles. Although PLA enzymes, particularly cytosolic PLA (cPLAα), have long been implicated in inflammation by driving arachidonic acid metabolism, the precise biological roles of sPLAs have remained a mystery over the last few decades. Recent studies employing mice gene-manipulated for individual sPLAs, in combination with mass spectrometric lipidomics to identify their target substrates and products in vivo, have revealed their roles in diverse biological events, including immunity and associated disorders, through lipid mediator-dependent or -independent processes in given microenvironments. In this review, we summarize our current knowledge of the roles of sPLAs in various immune responses and associated diseases.

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“…Human sPLA 2 s exhibit different enzymatic properties (11) as well as unique tissue and cellular distributions (10), suggesting distinct physiological roles for each enzyme. Besides their role in lipid mediator production, accumulating evidence indicates that sPLA 2 s participate in innate immunity, especially in the first line of host defense against bacteria and other pathogens (12)(13)(14)(15)(16)(17)(18)(19)(20)(21).…”

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In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A ₂

et al. 2015

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We have previously shown that secreted phospholipases A 2 (sPLA 2 s) from animal venoms inhibit the in vitro development of Plasmodium falciparum, the agent of malaria. In addition, the inflammatory-type human group IIA (hGIIA) sPLA 2 circulates at high levels in the serum of malaria patients. However, the role of the different human sPLA 2 s in host defense against P. falciparum has not been investigated. We show here that 4 out of 10 human sPLA 2 s, namely, hGX, hGIIF, hGIII, and hGV, exhibit potent in vitro anti-Plasmodium properties with half-maximal inhibitory concentrations (IC 50 s) of 2.9 ؎ 2.4, 10.7 ؎ 2.1, 16.5 ؎ 9.7, and 94.2 ؎ 41.9 nM, respectively. Other human sPLA2s, including hGIIA, are inactive. The inhibition is dependent on sPLA 2 catalytic activity and primarily due to hydrolysis of plasma lipoproteins from the parasite culture. Accordingly, purified lipoproteins that have been prehydrolyzed by hGX, hGIIF, hGIII, and hGV are more toxic to P. falciparum than native lipoproteins. However, the total enzymatic activities of human sPLA 2 s on purified lipoproteins or plasma did not reflect their inhibitory activities on P. falciparum. For instance, hGIIF is 9-fold more toxic than hGV but releases a lower quantity of nonesterified fatty acids (NEFAs). Lipidomic analyses of released NEFAs from lipoproteins demonstrate that sPLA 2 s with anti-Plasmodium properties are those that release polyunsaturated fatty acids (PUFAs), with hGIIF being the most selective enzyme. NEFAs purified from lipoproteins hydrolyzed by hGIIF were more potent at inhibiting P. falciparum than those from hGV, and PUFA-enriched liposomes hydrolyzed by sPLA 2 s were highly toxic, demonstrating the critical role of PUFAs. The selectivity of sPLA 2 s toward lowand high-density (LDL and HDL, respectively) lipoproteins and their ability to directly attack parasitized erythrocytes further explain their anti-Plasmodium activity. Together, our findings indicate that 4 human sPLA 2 s are active against P. falciparum in vitro and pave the way to future investigations on their in vivo contribution in malaria pathophysiology.

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Lack of group X secreted phospholipase A2 increases survival following pandemic H1N1 influenza infection

Cited by 22 publications

References 72 publications

Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

The Roles of the Secreted Phospholipase A2 Gene Family in Immunology

In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A ₂

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Lack of group X secreted phospholipase A2 increases survival following pandemic H1N1 influenza infection

Cited by 22 publications

References 72 publications

Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

Impaired heterologous immunity in aged ferrets during sequential influenza A H1N1 infection

The Roles of the Secreted Phospholipase A2 Gene Family in Immunology

In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A 2

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Product

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In Vitro Anti-Plasmodium falciparum Properties of the Full Set of Human Secreted Phospholipases A ₂