Thomas W. Molitor

Central Nervous System Tuberculosis: Pathogenesis and Clinical Aspects

SUMMARY Tuberculosis of the central nervous system (CNS) is a highly devastating form of tuberculosis, which, even in the setting of appropriate antitubercular therapy, leads to unacceptable levels of morbidity and mortality. Despite the development of promising molecular diagnostic techniques, diagnosis of CNS tuberculosis relies largely on microbiological methods that are insensitive, and as such, CNS tuberculosis remains a formidable diagnostic challenge. Insights into the basic neuropathogenesis of Mycobacterium tuberculosis and the development of an appropriate animal model are desperately needed. The optimal regimen and length of treatment are largely unknown, and with the rising incidence of multidrug-resistant strains of M. tuberculosis, the development of well-tolerated and effective antibiotics remains a continued need. While the most widely used vaccine in the world largely targets this manifestation of tuberculosis, the BCG vaccine has not fulfilled the promise of eliminating CNS tuberculosis. We put forth this review to highlight the current understanding of the neuropathogenesis of M. tuberculosis, to discuss certain epidemiological, clinical, diagnostic, and therapeutic aspects of CNS tuberculosis, and also to underscore the many unmet needs in this important field.

The opioid–cytokine connection

Opioids (exogenous opiates and endogenous opioid peptides) have a diversity of effects on the immune system. Although numerous studies have shown that opioid-induced immunosuppression can be mediated indirectly via the central nervous system (CNS) or through direct interactions with immunocytes, the precise cellular mechanisms underlying the immunomodulatory effects of opioids are largely unknown. In recent years, investigations from several laboratories have indicated that opioids can operate as cytokines, the principal communication signals of the immune system. All of the major properties of cytokines are shared by opioids, i.e., production by immune cells with paracrine, autocrine, and endocrine sites of action, functional redundancy, pleiotropy and effects that are both dose- and time-dependent. Studies of the effects of opioids on peripheral blood mononuclear cells (PBMC) or brain cells cocultured with HIV-infected cells suggest that some of the immunoregulatory actions of opioids are mediated by ultrahigh affinity receptors on PBMC and glial cells. Because the CNS is populated predominantly by astroglia and microglia which have properties of immune cells, it is possible that certain of the CNS effects of opioids involve cytokine-like interactions with glial cells. Although there is mounting evidence supporting the concept that opioids are members of the cytokine family, the relative contribution of the opioids to immunoregulation remains unclear. The importance of opiate addiction in the AIDS epidemic means that gaining a better understanding of the mechanisms of opioid-induced immunomodulation is of more than academic interest.

Experimental porcine reproductive and respiratory syndrome virus infection in one-, four-, and 10-week-old pigs.

One-, 4-, and lo-week-old pigs were exposed to porcine reproductive and respiratory syndrome virus (PRRSV) to determine the effect of age on clinical signs, hematologic alterations, the onset and duration of viremia, routes of virus shedding, antibody production, and microscopic lesions produced by PRRSV isolate ATCC VR-2332. The response to PRRSV infection was similar among age groups. Fever, usually prolonged, and a marked dyspnea with cutaneous erythema when restrained for sample collection were the most consistent clinical signs. Prolonged periocular edema was unique to the 1-week-old pigs. The white blood cell count was decreased on day 4 postexposure (PE) due to decreases in neutrophils and lymphocytes. The virus was isolated from buffy coats at day 1 PE and was isolated from serum, buffy coat, or plasma at each sample collection period through the end of the trial (day 28 PE). Virus was most consistently isolated from lung, lymph node, spleen, and tonsil on day 7 PE and exclusively from lymph node, spleen, and tonsil on day 28 PE. Virus was infrequently isolated from urine and fecal and nasal swabs. Consistent microscopic changes in all age groups included interstitial pneumonia and lymph node hypertrophy and hyperplasia on days 7 and 28 PE, lymph node necrosis on day 7 PE, and subacute mononuclear myocarditis on day 28 PE. Findings presented here indicate that interstitial pneumonia, lymphoid necrosis, and mononuclear myocarditis are characteristic lesions of PRRSV isolate ATCC VR-2332 infection in 1-, 4-, and lo-week-old pigs.

A modified serum neutralization test for the detection of antibody to porcine reproductive and respiratory syndrome virus in swine sera

Various conditions were evaluated and modified to improve the sensitivity of the serum neutralization (SN) test for detecting antibody in pigs infected with porcine reproductive and respiratory syndrome virus (PRRSV). Higher SN titers were consistently obtained by the addition of 20% fresh swine serum to the virus diluent and by the use of a permissive cell clone (MARC-145) derived from the MA-104 cell line. Test sera used to assess the SN test were obtained from 2 groups of 3-week-old pigs infected intranasally with PRRSV (MN-1b). Using the modified method, SN antibody was first detected 9–11 days postinoculation (PI), with a peak evident at 11–21 days PI. The antibody subsequently declined, and a second peak was observed between 41 and 45 days PI. The first antibody peak was not observed and the SN antibody was only detectable between 32 and 41 days PI when the test was done with 20% heated swine serum or without supplemental swine serum. The SN antibody during 2–3 weeks PI was found to be sensitive to 2-mercaptoethanol or anti-swine IgM treatment. The SN antibody titers were high when homologous PRRSV isolate was used in the test but were markedly low for heterologous PRRSV isolates. No difference in antibody titers was observed when homologous and heterologous PRRSV isolates were tested by indirect fluorescent antibody assay. These results indicate that the modified SN method is useful in detecting earlier and higher PRRSV antibody and that it can differentiate among PRRSV isolates.

Opiates and infection

This review on the effects of opiate use on infectious diseases discusses the complete spectrum of infections in the opiate user, including those of the lung, the GI tract, the skin, the skeletal system, and the CNS. There is both increased prevalence and increased severity of bacterial and viral infections in injection drug users with the outcome of increased morbidity and mortality. The experimental administration of opiates has lead to a greater understanding of the effects on susceptibility to and progression of infectious diseases. Animal models of opiate dependence and infection are reviewed with specific attention to cases in which the opiate-mediated effects are harmful and in which cases they are beneficial.

IFNγ inhibits porcine reproductive and respiratory syndrome virus replication in macrophages

SummaryThis study reports the effect of IFNγ on the replication of porcine reproductive and respiratory syndrome virus (PRRSV) in macrophages. Pretreatment with IFNγ profoundly affected PRRSV replication in porcine macrophages evaluated by reduction in titer and percentage of positive cells. The effect of IFNγ on PRRSV replication was both dose-dependent and related to the time of exposure. The mechanism of action was not due to blocking virus attachment. The inhibitory effect on PRRSV replication in macrophages suggests that IFNγ may play an important role in protection.

Current perspectives on the diagnosis and epidemiology of Mycoplasma hyopneumoniae infection

Abstract Mycoplasma hyopneumoniae is the principal aetiological agent of enzootic pneumonia (EP), a chronic respiratory disease that affects mainly finishing pigs. Although major efforts to control M. hyopneumoniae infection and its detrimental effects have been made, significant economic losses in pig production worldwide due to EP continue. M. hyopneumoniae is typically introduced into pig herds by the purchase of subclinically infected animals or, less frequently, through airborne transmission over short distances. Once in the herd, M. hyopneumoniae may be transmitted by direct contact from infected sows to their offspring or between pen mates. The ‘gold standard’ technique used to diagnose M. hyopneumoniae infection, bacteriological culture, is laborious and is seldom used routinely. Enzyme-linked immunosorbent assay and polymerase chain reaction detection methods, in addition to post-mortem inspection in the form of abattoir surveillance or field necropsy, are the techniques most frequently used to investigate the potential involvement of M. hyopneumoniae in porcine respiratory disease. Such techniques have been used to monitor the incidence of M. hyopneumoniae infection in herds both clinically and subclinically affected by EP, in vaccinated and non-vaccinated herds and under different production and management conditions. Differences in the clinical course of EP at farm level and in the efficacy of M. hyopneumoniae vaccination suggest that the transmission and virulence characteristics of different field isolates of M. hyopneumoniae may vary. This paper reviews the current state of knowledge of the epidemiology of M. hyopneumoniae infection including its transmission, infection and seroconversion dynamics and also compares the various epidemiological tools used to monitor EP.

Immunity to PRRSV: Double-edged sword

Abstract The immune system is a double-edged sword for porcine reproductive and respiratory syndrome virus (PRRSV) infection. On one edge PRRSV has a predilection for immune cells and the disease manifestations can be linked directly to changes in the immune system. PRRSV appears to replicate extensively, if not exclusively, in cells of the immune lineage, notably macrophages; the direct replication of which may lead to immunosuppression, precipitate secondary infection and/or mediate disease. On the other edge, the virus stimulates immunity post-infection that protects an animal from re-infection. A vast array of structural and functionally distinct antibody specific to PRRSV are generated following infection or vaccination. Discrete populations of functional antibodies appear at different times and possibly reflect reactivity to different PRRSV polypeptides. Cell-mediated immune responses specific to PRRSV can be detected in various exposed pigs as well. Thus, the immune system appears to be intimately involved in both the disease process and protection from disease. It is unclear at this state of understanding what immune compartment provides protective immunity. Is it humoral (i.e. antibodies), selective functionally distinct populations of antibodies specific for selected PRRSV polypeptides or is cellular immunity essential for protection, or both. This review will attempt to summarize the current state of knowledge of the complex interaction of the immune system and PRRSV.

Stress and Pathogenesis of Infectious Disease

Abstract Despite inherent difficulties in defining and measuring stress, a scientific framework has been provided in recent years for understanding how disruptive life experiences might be translated into altered susceptibility to infectious diseases. Studies of the effects of stress on pathogenesis of infectious disease are highly relevant to assessment of the biological importance of the immune impairments that have been associated with stress. With a few notable exceptions, investigations of viral infections in humans and in animal models support the hypothesis that stress promotes the pathogenesis of such infections. Similar conclusions can be drawn from studies of bacterial infections in humans and animals and from a small number of studies of parasitic infections in rodent models. While many of these studies have substantial limitations, the data nonetheless suggest that stress is a potential cofactor in the pathogenesis of infectious disease. Given recent unprecedented advances in the neurosciences, in immunology, and in the field of microbial pathogenesis, the relationship between stress and infection should be a fruitful topic for interdisciplinary research.

Mechanisms of morphine-induced immunomodulation

The concept of opiates as immunomodulatory agents dates to the turn of this century [l, 21. By the 194Os, many studies had been carried out on the effects of opiates on immune cells and on resistance of animals to infection [reviewed in Ref. 31. Also, most of the infectious disease complications of intravenous opiate abuse were well recognized [4]. Several decades elapsed, however, before interest in this topic was rekindled by the observation that cellmediated immune function is impaired in heroin addicts [5] and by reports in 1979 and 1980 that the major cell types involved in cell-mediated immunityT-lymphocytes and mononuclear phagocytes-possess opiate receptors [6-8]. Thus, the stage was set in 1981, the outset of the acquired immunodeficiency syndrome (AID%) epidemic, for intensive research in this area of immunology, once it became established that injection drug use was a prominent risk factor for this devastating infectious disease [9]. In addition to the potential relevance of opiateinduced immunomodulation to AIDS, progress in this area has been spurred by developments in two related fields. First, major advances have been made in the field of opiate pharmacology, especially in the delineation of selective classes of opioid receptors [reviewed in Ref. lo]. Second, new concepts have been derived from the field of “psychoneuroimmunology” regarding bidirectional communication between the neuroendocrine and immune systems [reviewed in Refs. 11 and 121. Studies in this multidisciplinary area of research have demonstrated a dynamic interaction between these two systems through chemical mediators, including endogenous opioid peptides. Not only have all three classes of endogenous opioid peptides been shown to affect immune cell function, but immunocytes