Platelets Help Tackle Bacteria

The notion that platelets may cooperate with other cells to clear blood-borne bacteria came from observations in the liver, said study lead Paul Kubes, an immunologist at the University of Calgary. While performing microscopy of specialized liver phagocytes called Kupffer cells, Kubes’ team noticed an unusual interaction between the phagocytes and platelets.

Kupffer cells sit in liver blood vessels, helping to capture and kill bacteria streaming past in the blood. Using intravital microscopy, the scientists saw that in uninfected mice, platelets performed what they termed a “touch and go” maneuver—interacting briefly with the Kupffer cells, but quickly disengaging and flowing away in the blood. But when mice were infected with certain types of bacteria—either Bacillus cereus or methicillin-resistant Staphylococcus aureus (MRSA), though not methicillin-susceptible S. aureus—the platelets formed long-term interactions with the Kupffer cells, engulfing the bacteria snagged from the blood.

Two different platelet receptors—already known to be important in platelets’ ability to staunch bleeding—mediated the two types of interactions the researchers saw. Kupffer cells collect von Willebrand Factor (vWF), a free-floating blood glycoprotein, on their surface. The “touch and go” behavior Kubes’s team saw involved the binding of vWF to platelets’ glycoprotein Ib (GpIb), which facilitates platelet aggregation at wound sites. In mutant mice missing GpIb, platelet “touch and go” no longer occurred. But the long-term congregating the scientists saw in B. cereus-infected mice required vWF-binding by the integrin GpIIb-GpIIIa, which also aids platelet aggregation.

The platelets, it turns out, were performing a life-enhancing function. When the researchers depleted platelets or used GpIb-deficient mice and infected them with B. cereus, these mice succumbed to infection at much higher rates. Platelet-depleted mice all died within 4 hours of infection, while over 80 percent of GpIb-deficient mice died within 4 hours—though less than 10 percent of wild type mice died at 4 hours.  Unlike wild type mice, mice lacking GpIb also couldn’t clear bacteria from their blood within 4 hours, suggesting that the platelets’ ability to interact with Kupffer cells was integral to fighting bacterial infection.

GpIb and GpIIb are “carrying members of the hemostatic repertoire of platelets—but here they fulfill an innate immune function”—highlighting platelets’ dual role, said Guy Zimmerman, an immunologist at the University of Utah, who did not participate in the study. However, he cautioned that it’s too soon to know whether platelets and Kupffer cells collaborate similarly in humans. Additionally, Zimmerman noted that the work will need to be extended to more types of bacteria, as the research focused on two gram-positive species, but many types seen by the liver will be gut-associated gram-negative species such as Escherichia coli.

If human platelets perform a similar function, patients with already-suppressed immune systems might suffer further from drugs that inhibit platelet function, such as aspirin, Kubes said. It’s an important question, acknowledged Watson. But he noted that there are many ways of activating GpIIb binding, making it unlikely that aspirin drastically affects platelets’ immune functions in healthy people. Instead, he said, the work suggests that in cases of trauma, it may be that platelets must be replaced to prevent both bleeding and infection.

Understanding the mechanism behind the platelets’ decision to aggregate on the bacteria-covered Kupffer cells could allow researchers to design a therapy to “favorably affect immune defenses without out affecting thrombotic potential,” speculated Zimmerman.

C.H.Y. Wong, et al. “Nucleation of platelets with blood-borne pathogens on Kupffer cells precedes other innate immunity and contributes to bacterial clearance,” Nature Immunology, doi: 10.1038/ni.2631, 2013.