The nocardiae are bacteria belonging to the aerobic actinomycetes. They are an important part of the normal soil microflora worldwide. The type species, Nocardia asteroides, and N. brasiliensis, N. farcinica, N. otitidiscaviarum, N. nova, and N. transvalensis cause a variety of diseases in both normal and immunocompromised humans and animals. The mechanisms of pathogenesis are complex, not fully understood, and include the capacity to evade or neutralize the myriad microbicidal activities of the host. The relative virulence of N. asteroides correlates with the ability to inhibit phagosome-lysosome fusion in phagocytes; to neutralize phagosomal acidification; to detoxify the microbicidal products of oxidative metabolism; to modify phagocyte function; to grow within phagocytic cells; and to attach to, penetrate, and grow within host cells. Both activated macrophages and immunologically specific T lymphocytes constitute the major mechanisms for host resistance to nocardial infection, whereas B lymphocytes and humoral immunity do not appear to be as important in protecting the host. Thus, the nocardiae are facultative intracellular pathogens that can persist within the host, probably in a cryptic form (L-form), for life. Silent invasion of brain cells by some Nocardia strains can induce neurodegeneration in experimental animals; however, the role of nocardiae in neurodegenerative diseases in humans needs to be investigated.

A survey of members of the Infectious Diseases Society of America indicated that nocardial infections are not rare. Probably between 500 and 1,000 cases are recognized in the United States each year, of which 85% are serious pulmonary or systemic infections. Although nocardial infections are usually opportunistic infections in the compromised host, at least 15% of the infections in this series occurred in patients without a definable predisposing condition. Nocardial infections occurred in a random geographic distribution within this country, with affected males outnumbering females by 3:1. Most patients were between the ages of 21 and 50 years; however, the age range was broad. The number and variety of infections caused by Nocardia species other than Nocardia species other than Nocardia asteroides have been underestimated. Between 8.6% and 18.8% of pulmonary-systemic infections in this series were caused by species of Nocardia other than N. asteroides.

SUMMARYAs current research illuminates the dynamic interplay between the innate and acquired immune responses, the interaction and communication between these two arms has yet to be fully investigated. Polymorphonuclear neutrophils (PMNs) and interferon-c (IFN-c) are known critical components of innate and acquired immunity, respectively. However, recent studies have demonstrated that these two components are not entirely isolated. Treatment of PMNs with IFN-c elicits a variety of responses depending on stimuli and environmental conditions. These responses include increased oxidative burst, differential gene expression, and induction of antigen presentation. Many of these functions have been overlooked in PMNs, which have long been classified as terminal phagocytic cells incapable of protein synthesis. As this review reports, the old definition of the PMN is in need of an update, as these cells have demonstrated their ability to mediate the transition between the innate and acquired immune responses.

Survival from murine pulmonary nocardiosis is highly dependent on CXC chemokine receptor-2 (CXCR2) ligand-mediated neutrophil chemotaxis and subsequent clearance of the infectious agent Nocardia asteroides. Intratracheal inoculation of N. asteroides rapidly up-regulated the CXC chemokines macrophage inflammatory protein-2 (MIP-2) and KC within 24 h, with levels remaining elevated through day 3 before returning to near baseline levels by day 7. Coinciding with elevated MIP-2 and KC were the rapid recruitment of neutrophils and clearance of the organism. Anti-Ly-6G Ab-mediated neutrophil depletion before bacterial challenge resulted in strikingly increased mortality to N. asteroides infection. The relative contribution of MIP-2 in neutrophil recruitment was examined by anti-MIP-2 Ab treatment before nocardial infection. MIP-2 neutralization had no detrimental effects on survival, neutrophil recruitment, or bacterial clearance, suggesting the usage of additional or alternative CXCR2-binding ligands. The importance of the CXC family of chemokines was determined by the administration of an anti-CXCR2 Ab capable of blocking ligand binding in vivo. Anti-CXCR2 treatment greatly increased mortality by preventing neutrophil migration into the lung. Paralleling this impaired neutrophil recruitment was a 100-fold increase in lung bacterial burden. Combined, these observations indicate a critical role for neutrophils and CXC chemokines during nocardial pneumonia. These data directly link CXCR2 ligands and neutrophil recruitment and lend further support to the concept of CXC chemokine redundancy. For infections highly dependent on neutrophils, such as nocardial pneumonia, this is of critical importance.

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The persistence of numerous pathogenic bacteria important in disease states, such as tuberculosis, in humans and domestic animals has been ascribed to an inhibition of fusion between the phagosomal vesicles containing the bacteria and lysosomes in the host cells [Elsbach, P. & Weiss, J. (1988) Biochim. Biophys. Adia 974, 29-52; Thoen, C. 0.(1988)J. Am. Vet. Med. Assoc. 193, 1045Assoc. 193, -1048. In tuberculosis this effect has been indirectly attributed to the production of cord factor (a,a-trehalose 6,6'-dimycolate). We show here that cord factor is extraordinarily effective at inhibiting Ca2+-induced fusion between phospholipid vesicles and suggest a mechanism by which cord factor confers this effect. These findings are likely to be important in our understanding of the pathogenesis and treatment of many diseases of bacterial etiology.

Nocardia asteroides can cause infections in the brain of humans and a variety of animals. In mice, invasion of the central nervous system results in specific neurologic signs. Following intravenous injection of various doses of log-phase N. asteroides GUH-2 into female BALB/c mice, localization and growth of nocardial cells within the brains were determined, histopathological sections were prepared, and Nissl substance and tyrosine hydroxylase immunoreactivity were observed. Mice were monitored for the development of neurologic signs, and their responsiveness to L-dopa was determined. It was shown that nocardial cells became localized within specific regions of the brain and then underwent rapid growth followed by a delayed clearance, and there was no inflammatory response at the site of invasion for 24 h. Mice that received a subclinical dose of nocardiae developed specific neurologic signs that emerged following the elimination of nocardial cells from the brain. On the basis of the specific signs, mice could be divided into distinct groups. One group consisted of animals that had a form of hemiparesis that did not respond to L-dopa. They expressed a deviation of the head and a tendency to roll, and when suspended by the tail they would spin rapidly. The second group of mice developed a rhythmic, uncontrolled vertical shake of the head (four to five times per s) with tremulous movement, stooped posture, restlessness, and no signs of hemiparesis. The head shakes were temporarily stopped by treatment with L-dopa. Mice that expressed head shakes had a loss of Nissl substance and tyrosine hydroxylase immunoreactivity in the neurons of the substantia nigra and ventral tegmental areas of the brain. Hyaline inclusion bodies that resembled Lewy bodies were found in the neurons of mice with head shake 1 month after infection. Therefore, mice infected with N. asteroides may serve as a model for studying parkinsonian signs and other degenerative diseases involving extrapyramidal and pyramidal systems.animals and those observed with Parkinson's disease (PD) in humans might involve similar mechanisms.A review of the literature revealed that, in humans, N. asteroides can cause encephalitis with parkinsonian features (35). Richter et al. (35) reported on the following case. A 39-year-old male developed fever, myalgia, and arthralgia. Five days later, he experienced visual hallucinations and severe tremors developed. After 6 weeks of illness, his face was masklike, his speech was dysarthric, his movement was tremulous, and his muscle tone was increased. Generalized hyperreflexia with bilateral patellar and ankle clonus was noted. The patient experienced coarse and irregular tremors while at rest in all extremities including the head. N. asteroides was recovered from the cerebrospinal fluid, and the patient improved upon therapy with sulfadiazine (35). Furthermore, there are numerous reports in the literature describing involuntary, neurological manifestations in humans with brain infections caused by N. asteroides (1,17,26,34,...

There are three commonly recognized species ofNocardiathat cause disease in a large variety of animals including humans. In the United States, pulmonary or systemic nocardiosis in humans caused byN. asteroidesis most frequently diagnosed. It should be noted thatN. brasiliensiscan cause nocardiosis also. In Central and South America mycetomas induced byN. brasiliensisappear to be more prevalent even thoughN. asteroidescan be seen in this type of infection. Sporadic cases of both mycetoma and nocardiosis caused byN. caviaehave been reported. These three species ofNocardiaappear to be present in the soils of most countries; butN. asteroidesis more frequently isolated in the temperate climates whereasN. brasiliensispredominates in the tropical and subtropical regions of the world. No specific geographic distribution has been noted withN. caviae. Infections involving these three species of bacteria are, therefore, worldwide in occurrence. Even though nocardial infections in both humans and animals were recognized as early as 1888, traditionally, they have been considered rare in frequency as compared to many other infectious diseases. This is a perception that probably is not accurate. During the past twenty years, greater diagnostic awareness combined with more intensive medical and veterinary surveillance have resulted in significantly increased recognition of disease caused by these aerobic actinomycetes.