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Natural Killer Cells Promote Tissue Injury and Systemic Inflammatory Responses During Fatal Ehrlichia-Induced Toxic Shock-Like Syndrome
Stevenson HL, Estes MD, Thirumalapura NR, Walker DH, Ismail N.
Department of Pathology, University of Texas Medical Branch, the Sealy Center for Vaccine Development, and the Center for Biodefense and Emerging Infectious Diseases, Galveston, Texas; and the Departments of Pathology, Microbiology and Immunology, Meharry Medical College, Nashville, Tennessee Department of Pathology, University of Texas Medical Branch, Galveston, Texas, USA.
Am J Pathol. 2010 Aug;177(2):766-776, DOI: 10.2353/ ajpath.2010.091110
                                            

A synopsis written by co-author and ASIP trainee Dr. Heather Stevenson, at the University of Texas Medical Branch in Galveston, TX

It is a very exciting time in the field of ehrlichiosis, with many recent discoveries providing answers to previously controversial or unknown questions.  Ehrlichia are obligately intracellular bacteria that lack genes for lipopolysaccharide (LPS) and peptidoglycan, and reside within the early endosomes of monocytic cells inhibiting phagolysosome fusion.  These bacteria are transmitted by ticks; the primary vector is Amblyomma americanum.  The clinical presentation of human monocytotropic ehrlichiosis (HME) may be nonspecific, and the disease is difficult to diagnose.  The intracellular microcolonies of bacteria that are prototypical of the disease are rarely identified in blood smears, a characteristic clinical sign, such as a rash, is observed in relatively few patients, and history of a tick bite may be lacking. 

The clinical presentation of the disease is variable.  Interstitial pneumonia, hepatic dysfunction, aseptic meningitis, and hemorrhages have been described.  The severity of the disease is greater in elderly and immunocompromised patients; however, even in immunocompetent patients HME can be fatal.  Even with susceptibility of Ehrlichia chaffeensis to doxycycline, the case fatality rate is still approximately 3%.  Overwhelming ehrlichial infections occur mainly in immunocompromised patients, and in contrast fatal ehrlichiosis in immunocompetent patients occurs with a low bacterial load.  In addition, hepatocytes have been observed to undergo apoptosis without evidence of ehrlichial infection.  These characteristics, along with the clinical presentation resembling toxic shock-like syndrome, support the hypothesis that dysregulation of the host immune response leads to tissue damage and eventually multi-system organ failure.

One of the primary goals of our laboratories is to gain a better understanding of how this immune-mediated pathology is induced.  Cell mediated immunity, orchestrated mainly by CD4⁺ Th1 cells, is required for protection against severe disease.  Mouse models of HME also allow the determination of the factors that lead to the development of severe ehrlichiosis, which include high concentrations of TNF-α and IL-10 in the serum, a high frequency of TNF-α producing CD8⁺ T cells in the spleen, low IL-12 levels in the spleen, and a 40-fold decrease in the number of IFN-g producing CD4⁺ T cells.  Recently, we observed an expansion of NK cells in the liver, one of the primary sites of Ehrlichia-induced pathology and decided to study the specific role of these cells during the disease process.  We used an established mouse model to compare differences in the immune response between wild-type and NK cell-depleted mice.   Depletion of NK cells prevented development of severe liver injury, resulted in decreased serum levels of interferon-γ, TNF-α and IL-10, and enhanced bacterial elimination.   Even with these significant decreases in the disease pathology, the NK cell-depleted mice still succumbed to ehrlichial infection, most likely because NK cells were able to replicate in vivo to such high numbers, they were unable to be completely depleted.  We also have identified other cells, such as cytotoxic CD8⁺ T cells that are pathogenic, indicating that not only one immune cell type is responsible for initiating fatal disease.  These data indicate that NK cells promote immunopathology and defective anti-ehrlichial immunity, possibly via decreasing the protective immune response mediated by interferon-γ producing CD4⁺ Th1 and NKT cells.  In several different mouse strains, induction of Th1 immunity has been essential to host survival, and when CD4⁺ T cell help is compromised, whether by NK cells or cytotoxic CD8⁺ T cells, the immune response becomes dysregulated and destructive.  Overall, the pathogenesis of ehrlichial disease appears to be multifactorial as in other septic conditions, which explains the inability to completely control the disease by inhibiting one component such as TNF-α, CD8⁺ T cells, or NK cells.