Friday, October 30, 2009

Infectious Fatigue

Between 1 and 4 million Americans suffer from Chronic Fatigue Syndrome (CFS), which is a “complicated disorder characterized by extreme fatigue that may worsen with physical or mental activity, but doesn't improve with rest.” (Mayo Clinic). The cause is unknown and there is no known cure. An infectious cause has been suspected and sought for decades without success. The recent discovery of XMRV, new retrovirus found in some prostate cancer patients (but not others) prompted Lombardi and colleagues to test for its involvement with CFS. They performed PCR for XMRV gag, which encodes structural viral proteins, on peripheral blood mononuclear cells from CFS patients in a repository at their Whittemore Peterson Institute. Of 101 CFS samples tested, 68 (67%) were positive in contrast to only 8 out of 218 samples (4%) from healthy donors. Another viral gene, env, was also detected in most CFS patients positive for gag as were the proteins encoded by these genes. Oddly, patient sample WPI-1118 is negative for gag and env (Fig 1) but weakly positive by cytometry (Fig 2 A & D) and clearly positive by Western protein blot (Fig 4 A). Both B and T lymphocytes express XMRV proteins. And, for what it's worth, some CFS patient cells make virus that can productively infect other cells (shown, from Figure 3 B & C, electron micrographs of budding virus particles).

The authors note in their introduction that “patients with CFS often have active β herpesvirus infections, suggesting an underlying immune deficiency”. This increases the odds that XMRV is an opportunistic infection. The authors return to this question in their closing discussion, asking “Is XMRV infection a causal factor in the pathogenesis of CFS or a passenger virus in the immunosuppressed CFS patient population?” Stand by.

Lombardi VC, Ruscetti FW, Das Gupta J, Pfost MA, Hagen KS, Peterson DL, Ruscetti SK, Bagni RK, Petrow-Sadowski C, Gold B, Dean M, Silverman RH, Mikovits JA. "Detection of an Infectious Retrovirus, XMRV, in Blood Cells of Patients with Chronic Fatigue Syndrome". Science. 2009 Oct 8.

Wednesday, October 7, 2009

Infecting the Protectors (fluNK)

Influenza (flu) is typically transmitted through the air, infecting lung epithelial cells. Natural Killer (NK) cells are lymphocytes that help protect from flu, especially early after infection, by killing infected cells and secreting cytokines and chemokines that inhibit virus replication. Here, Guo and colleagues ask whether NK might themselves be infected by flu. They confirmed that NK express on their surface sialic acids, which serve as flu receptors by binding hemagluttinin (HA). By microscopy, they examined mice infected with PR8, a strain originating from the human flu virus A/PR/8/34 and detected flu virus protein M2 inside of NK cells within the lungs of infected mice. NK possess several activating receptors including NCR1, NKG2D, Ly49D and inhibiting receptors including NKG2A, Ly49A. Flow cytometry demonstrated that PR8 did not modulate these receptors or developmental markers.
However, infection did alter the effector functions of NK cells. Infected NK cells were less capable of killing cells from 3 target lines, cells susceptible because they either express ligands for NK activating receptors or fail to express ligands for NK inhibiting receptors (Figure 5, shown). EL4 cells express a transfected H60, which binds the activating receptor NKG2D; YAC-1 cells express H60 constitutively, and RMA-S cells express very little HLA class I protein, which binds the inhibitory Ly49 receptors. The authors and others had previously shown
that the 85 kDa subunit of phosphotidyl inositol 3-kinase (PI3K-p85) was critical for NK effector functions, including killing and production of cytokines/chemokines, and that flu NS1 protein interacted with this kinase. Surprisingly, a PR8 virus with a mutated NS1 protein was even more effective in suppressing NK effector functions, leaving the mechanism of inhibition to be determined.
Guo H, Kumar P, Moran TM, Garcia-Sastre A, Zhou Y, Malarkannan S. “The functional impairment of natural killer cells during influenza virus infection.” Immunol Cell Biol. 2009 Sep 1.