Jill D. Henning

Epinephrine promotes COX-2-dependent immune suppression in myeloid cells and cancer tissues

Activation of the sympathetic nervous system (e.g., due to stress) has been implicated in cancer progression and recurrence, but its cancer-promoting effects have been variable between different studies. Here, we report that although catecholamines, mediators of systemic sympathetic activity, display only weak immunosuppressive impact on their own, their combination with inflammatory signals leads to the induction of COX-2 and multiple COX-2-dependent suppressive factors in human myeloid cells and cancer tissues. Human macrophages exposed to epinephrine and TNFα, or macrophages generated in 6day cultures in the presence of epinephrine, expressed high levels of COX-2, IDO and IL-10, and strongly suppressed both the proliferation and IFNγ production of CD8+ T cells. These suppressive effects of epinephrine were counteracted by celecoxib, a selective inhibitor of COX-2 activity, which inhibited the induction of immunosuppressive factors (including the elevated expression of COX-2 itself) and the ability of epinephrine-exposed macrophages to suppress CD8+ T cell responses. The activation of the COX-2/PGE2 system and COX-2-dependent suppressive events were also observed in ex vivo human breast and colon cancer explant cultures and were similarly counteracted by celecoxib. Our preliminary data also indicate elevated COX-2 expression in mammary tumors of chronic stress-exposed mice. The current demonstration of the interplay between inflammation and the induction of immunosuppressive factors by catecholamines suggest a contextual impact of stress, helping to explain variable results of epidemiologic studies of the link between sympathetic activity and cancer progression, and implicating COX-2 blockade as a potential means to mitigate stress-related immune suppression.

Human herpesvirus 8 establishes a latent infection in prostates of Tobago men resulting in increased macrophage infiltration.

The Caribbean island of Tobago, which is 97% African ancestry, has one of the highest rates of prostate cancer in the world. We have previously reported that human herpesvirus 8 (HHV‐8) infection is significantly associated with prostate cancer in Tobago. In this study, we extend those results testing the hypothesis that HHV‐8 seropositive Tobagonian men have a chronic HHV‐8 infection in their prostates that is associated with increased inflammation.

Implementation of a sampling strategy to detect West Nile virus in oral and cloacal samples in live song birds

In 1999, West Nile virus (WNV) first appeared in the United States and has subsequently infected more than a million people and untold numbers of wildlife. Though primarily an avian virus, WNV can also infect humans and horses. The current status of WNV and its effects on wildlife in Pennsylvania (PA) is sparsely monitored through sporadic testing of dead birds. In order to acquire a more comprehensive understanding of the status of WNV in wild birds, a study was designed and implemented to sample populations of migratory and local birds at Powdermill Nature Reserve near Rector, PA. Resident and migratory bird species totaling 276 individuals were sampled cloacally and orally to compare the effectiveness of sampling methods. The presence of WNV was tested for using RT-PCR. Two positive samples were found, one from a migrating Tennessee warbler and another from an American robin. The low infection rates indicate that WNV may not be a critical conservation concern in the Westmoreland County region of PA. There was also agreement between oral and cloacal swabs, which provides support for both methods. This study describes a surveillance method that is easily incorporated into any banding operation and which determines the risks of WNV to various bird populations.

Wild snakes harbor West Nile virus

West Nile virus (WNV) has a complex eco-epidemiology with birds acting as reservoirs and hosts for the virus. Less well understood is the role of reptiles, especially in wild populations. The goal of our study was to determine whether a wild population of snakes in Pennsylvania harbored WNV. Six species of snakes were orally sampled in the summer of 2013 and were tested for the presence of WNV viral RNA using RT-PCR. Two Eastern Garter Snakes, Thamnophis sirtalis sirtalis tested positive for viral RNA (2/123, 1.62%). These results indicate a possible role for snakes in the complex transmission cycle of WNV.

Detection of Lyme disease and anaplasmosis pathogens via PCR in Pennsylvania deer ked.

ABSTRACT: Borrelia burgdorferi and Anaplasma phagocytophilum are obligate intracellular parasites that maintain their life cycles in enzoonotic vector-host cycles with Ixodes scapularis as a vector. In addition to ticks, the hosts are commonly infested with insects from the Hippoboscidae family. This study confirms the presence of B. burgdorferi and A. phagocytophilum in deer keds (Lipoptena cervi) removed from white-tailed deer using PCR. Detection of these pathogens in deer ked represents a potential novel susceptibility of wildlife and also suggests the risk of transmission of these pathogens to humans and animals alike through the bite of an infected ectoparasite. This study represents the first instance in the U.S. of detection of tick-borne pathogens in a member of the Hippoboscid family.

Detection of Borrelia burgdorferi and Anaplasma phagocytophilum in the Black-Legged Tick, Ixodes scapularis, within Southwestern Pennsylvania

ABSTRACT: Prevalence studies of Borrelia burgdorferi and Anaplasma phagocytophilum have been rare for ticks from southwestern Pennsylvania. We collected 325 Ixodes scapularis ticks between 2011 and 2012 from four counties in southwestern Pennsylvania. We tested for the presence of Borrelia burgdorferi and Anaplasma phagocytophilum using PCR. Of the ticks collected from Pennsylvania, B. burgdorferi (causative agent of Lyme disease) was present in 114/325 (35%) and Anaplasma phagocytophilum (causative agent of Human Granulocytic Anaplasmosis) was present in 48/325 (15%) as determined by PCR analysis.

Chronic Inflammation in Cancer: The Role of Human Viruses

While the process of inflammation is a normal biological process to protect the body from harmful stimuli, chronic inflammation has been linked to a number of human diseases, including cancer. A number of agents can stimulate a chronic inflammatory response, which in turn promotes carcinogenesis. Here, we will describe how chronic inflammation is established through changes in cytokine signaling, perturbations of the NF-κB pathway, DNA damage, and physiological changes within the microenvironment and how these changes also contribute to tumorigenesis. In addition, we will describe the direct and indirect mechanisms by which infection by six viruses—Epstein-Barr, human herpesvirus-8, hepatitis B and C, human papilloma, and human T-lymphotropic virus type 1—induces chronic inflammation leading to tumor formation.

Abstract B006: Analysis of the interaction of human herpes virus 8 and gp130 in prostate cancer risk

Prostate cancer is the most common cancer among men in the United States and is second to lung cancer as a cause of cancer death. The occurrence of prostate cancer is not uniform among different races. It is more prevalent among African Americans than either Caucasians or Asians. This increased risk for prostate cancer among men of African descent is particularly strong in the Caribbean nation of Trinidad and Tobago where the prevalence of screening-detected prostate cancer was 3-fold higher among Tobago men of African descent compared to U.S. Caucasian men. In the present study we test the hypothesis that a polymorphism in the binding domain of gp130 in association with inflammation induced by HHV-8 increases the risk of prostate cancer. As a result, Tobago men with the high-risk gp130 allele whose prostates express HHV-8 proteins have an increased risk of prostate cancer (OR=3.1, 95% C.I. 1.18-8.11). In addition, studies in B cell lines derived from Tobago men with the three different genotypes showed that IL-6 causes a significant increase in cell division based on genotype with a resulting increase in STAT-3 activation via phosphorylation. These results will also aid in defining better a treatment plan for prostatic inflammation that is a result of viral infection and will provide a better understanding of disease progression. Citation Format: Jill D. Henning, Kathrine Kercher, Clareann H. Bunker, Robert E. Ferrel, Alan L. Patrick, Frank J. Jenkins. Analysis of the interaction of human herpes virus 8 and gp130 in prostate cancer risk [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B006.

Elevated serum PSA Is associated with human herpesvirus 8 infection and increased circulating cytokine levels in men from tobago

Serum‐prostate specific antigen (PSA) levels have been used for many years as a biomarker for prostate cancer. This usage is under scrutiny due to the fact that elevated PSA levels can be caused by other conditions such as benign prostatic hyperplasia and infections of or injury to the prostate. As a result, the identification of specific pathogens capable of increasing serum levels of PSA is important. A potential candidate responsible for elevated PSA is human herpesvirus 8 (HHV‐8). We have reported previously that HHV‐8 is capable of infecting and establishing a latent infection in the prostate. In this current study we test the hypothesis that HHV‐8 infection is associated with elevated PSA levels. Circulating cytokine levels between men with elevated PSA and controls are also compared.

Human herpesvirus 8 infection contributes to a T helper 2 immune response in men from Tobago with prostate cancer

To compare the cytokine profile between human herpesvirus 8 seropositive and seronegative men with and without prostate cancer.