Magnetic Resonance Imaging in Pediatric Acetabulum Fractures with Open Triradiate Cartilage-A Report of 3 Cases.

We present three cases of posterior wall acetabulum fractures occurring in pediatric patients with open triradiate cartilage for whom preoperative magnetic resonance imaging was obtained and open reduction and internal fixation was done. All patients had excellent outcomes at an average of 68-week follow-up. Failure to adequately recognize the severity of pediatric acetabulum fractures can lead to detrimental long-term sequelae in acetabular development when treated nonsurgically. Management of this rare injury is not well reported in the literature. We highlight the utility of MRI in evaluating potential nonosseous injury and examining the articular surface to guide surgical management.

The heat shock protein Hsc70-3 mediates an anti-apoptotic response critical for Plasmodium evasion of Anopheles gambiae immunity.

IMPORTANCE: Malaria transmission by Anopheles gambiae mosquitoes is very effective, in part because the parasite expresses a surface protein called Pfs47 that allows it to evade the mosquito immune system. Here we investigate how this protein changes the response of mosquito midgut epithelial cells to invasion by the parasite. Pfs47 is known to interact with P47Rec, a mosquito midgut receptor. We found that Pf47Rec inhibits caspase-mediated apoptosis by interacting with the Hsc70-3. This disrupts nitration of midgut epithelial cells invaded by the parasite and the release of hemocyte-derived microvesicles, which are critical for effective activation of the mosquito complement system that eliminates the parasite.

Plasmodium falciparum Gametes and Sporozoites Hijack Plasmin and Factor H To Evade Host Complement Killing.

Plasmodium parasites are the etiological agents of malaria, a disease responsible for over half a million deaths annually. Successful completion of the parasite's life cycle in the vertebrate host and transmission to a mosquito vector is contingent upon the ability of the parasite to evade the host's defenses. The extracellular stages of the parasite, including gametes and sporozoites, must evade complement attack in both the mammalian host and in the blood ingested by the mosquito vector. Here, we show that Plasmodium falciparum gametes and sporozoites acquire mammalian plasminogen and activate it into the serine protease plasmin to evade complement attack by degrading C3b. Complement-mediated permeabilization of gametes and sporozoites was higher in plasminogen-depleted plasma, suggesting that plasminogen is important for complement evasion. Plasmin also facilitates gamete exflagellation through complement evasion. Furthermore, supplementing serum with plasmin significantly increased parasite infectivity to mosquitoes and lowered the transmission-blocking activity of antibodies to Pfs230, a potent vaccine candidate currently in clinical trials. Finally, we show that human factor H, previously shown to facilitate complement evasion by gametes, also facilitates complement evasion by sporozoites. Plasmin and factor H simultaneously cooperate to enhance complement evasion by gametes and sporozoites. Taken together, our data show that Plasmodium falciparum gametes and sporozoites hijack the mammalian serine protease plasmin to evade complement attack by degrading C3b. Understanding of the mechanisms of complement evasion by the parasite is key to the development of novel effective therapeutics. IMPORTANCE Current approaches to control malaria are complicated by the development of antimalarial-resistant parasites and insecticide-resistant vectors. Vaccines that block transmission to mosquitoes and humans are a plausible alternative to overcome these setbacks. To inform the development of efficacious vaccines, it is imperative to understand how the parasite interacts with the host immune response. In this report, we show that the parasite can co-opt host plasmin, a mammalian fibrinolytic protein to evade host complement attack. Our results highlight a potential mechanism that may reduce efficacy of potent vaccine candidates. Taken together, our results will inform future studies in developing novel antimalarial therapeutics.

Transgenic Anopheles mosquitoes expressing human PAI-1 impair malaria transmission.

In mammals, the serine protease plasmin degrades extracellular proteins during blood clot removal, tissue remodeling, and cell migration. The zymogen plasminogen is activated into plasmin by two serine proteases: tissue-type plasminogen activator (tPA) and urokinase-type plasminogen activator (uPA), a process regulated by plasminogen activator inhibitor 1 (PAI-1), a serine protease inhibitor that specifically inhibits tPA and uPA. Plasmodium gametes and sporozoites use tPA and uPA to activate plasminogen and parasite-bound plasmin degrades extracellular matrices, facilitating parasite motility in the mosquito and the mammalian host. Furthermore, inhibition of plasminogen activation by PAI-1 strongly blocks infection in both hosts. To block parasite utilization of plasmin, we engineered Anopheles stephensi transgenic mosquitoes constitutively secreting human PAI-1 (huPAI-1) in the midgut lumen, in the saliva, or both. Mosquitoes expressing huPAI-1 strongly reduced rodent and human Plasmodium parasite transmission to mosquitoes, showing that co-opting plasmin for mosquito infection is a conserved mechanism among Plasmodium species. huPAI-1 expression in saliva induced salivary gland deformation which affects sporozoite invasion and P. berghei transmission to mice, resulting in significant levels of protection from malaria. Targeting the interaction of malaria parasites with the fibrinolytic system using genetically engineered mosquitoes could be developed as an intervention to control malaria transmission.

Beyond cuts and scrapes: plasmin in malaria and other vector-borne diseases.

Plasmodium and other vector-borne pathogens have evolved mechanisms to hijack the mammalian fibrinolytic system to facilitate infection of the human host and the invertebrate vector. Plasmin, the effector protease of fibrinolysis, maintains homeostasis in the blood vasculature by degrading the fibrin that forms blood clots. Plasmin also degrades proteins from extracellular matrices, the complement system, and immunoglobulins. Here, we review some of the mechanisms by which vector-borne pathogens interact with components of the fibrinolytic system and co-opt its functions to facilitate transmission and infection in the host and the vector. Further, we discuss innovative strategies beyond conventional therapeutics that could be developed to target the interaction of vector-borne pathogens with the fibrinolytic proteins and prevent their transmission.