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Electron microscopic studies of cystitis produced by instillation of Listeria monocytogenes into the urinary bladder of guinea pigs were carried out in order to investigate the epithelial phase of the infection. While bacteria lying free in the cytoplasm of epithelial cells showed no sign of damage and were able to multiply there, part of those in phagosomes of epithelial cells were killed. During the course of the infection the number of lysosomes, multivesicular bodies, Golgi complexes, and endoplasmic reticulum were increased in the bacteria-containing cells (epithelial activation). It is suggested that a variable epithelial phase is a characteristic feature of infections caused by intracellular parasitic bacteria when the port of the entry of the bacteria is an epithelial barrier.

Auf Grund des dargelegten statistisch beweiskraftigen Materials ergibt sich, das Kinder mit atiologisch anderweitig bisher nicht zu klarenden Cerebralschaden hohe Listeria-Agglutinationstiter und oft auch Komplementbindungstiter aufweisen. Die Titer sind mit groser Wahrscheinlichkeit relativ konstante Resttiter. Das Krankheitsbild dieser Kinder, die vorwiegend vom Lande stammen, zeigt gewisse klinische Gemeinsamkeiten, die weitgehende Parallelen in der Veterinar-Medizin finden. Eine Reihe rechnerischer Anhaltspunkte spricht fur die Spezifitat von Listeria-Titern.

Five methods have been used in an effort to reveal an antibody that could account for the features of acquired resistance to Listeria monocytogenes: (a) a comparison of the growth rates of Listeria in the spleens of mice infused repeatedly with normal or immune mouse serum; (b) measurement of peritoneal clearance of Listeria in the presence of normal or immune mouse serum; (c) the survival rate of Listeria in monolayers of mouse macrophages infected in the presence of normal or immune mouse serum; (d) the effect of injecting urea extracts of spleens and peritoneal macrophages of normal or immune mice on the survival and growth of Listeria in recipient animals; (e) a comparison of survival rates in lethally infected mice following the passive transfer of cells and serum from normal or immune donors. The only evidence of passive protection was obtained when intact living cells from immune donors were used for transfer under conditions which permitted them to interact with the parasite population.

The antigenic relationships between the different serotypes of Listeria monocytogenes and Staphylococcus aureus were investigated by means of agglutination, agglutinin-absorption, precipitation, and complement fixation tests. Reciprocal cross-reactions were demonstrated with serotypes 1, 2, and 3 of L. monocytogenes and many S. aureus strains, but not with serotypes 4a and 4b, using O suspensions of L. monocytogenes and autoclaved suspensions of S. aureus. Soluble heat-stable polysaccharide extracts, on the contrary, were quite specific in precipitin tests. Antisera against L. monocytogenes type 3 cross-precipitated unilaterally extracts of most S. aureus strains. In the absence of clear-cut serological species specificity in these two microorganisms, in their reactions with rabbit antisera, and with human sera from suspected cases of listeriosis, there is need for caution in the interpretation of positive serological tests as an aid to diagnosis.

Akut fieberhafte Erkrankungen wahrend der Schwangerschaft, besonders solche mit cystopyelitischen Beschwerden, geben anamnestisch einen wichtigen Hinweis.

A case of Listeria monocytogenes meningitis in the neonatal period, diagnosed primarily by blood culture, is presented. Recovery was uneventful. The organism showed in-vitro sensitivity to erythromycin, oxytetracycline, chlortetracycline, and penicillin, and was resistant to several sulfornamide compounds.

Experiments directed toward determining the lipids in extracts of Listeria monocytogenes containing monocytosis-producing agent (MPA) and the effect of these extracts on several biochemical parameters previously shown to change during experimental Listeria infection were conducted. MPA-containing extracts were found to be a complex of lipids with glycerides, glycolipids, and phospholipid being present. No common cell wall carbohydrates were found. A glyceride, designated glyceride A, was determined to cause the characteristic mononuclear response observed in mice injected with MPA-containing extracts. Fasted MPA-treated animals showed less gluconeogenesis than did controls. Blood glucose levels declined in MPA-treated animals. Increases observed in both blood urea nitrogen and plasma glutamic-pyruvic transaminase were greater in the control groups. Incorporation of 14 C-alanine into liver glycogen was depressed in MPA-treated animals. Liver steroid levels in the control groups increased during fasting and remained elevated for the duration of the experiments, while levels in the MPA-treated groups declined initially and showed no increase until 72 hr after injection. MPA appears to affect steroid metabolism and consequently the animals' homeostatic mechanisms seem to be impaired. Possibly as a consequence, carbohydrate metabolism is altered. The apparent effect of MPA on steroid metabolism and on the gluconeogenic process may indicate participation in the carbohydrate derangement observed in experimental Listeria infection.

Thymectomized adult rats which have been heavily irradiated and reconstituted with syngeneic bone marrow cells rapidly regain the ability to defend themselves against a primary infection with the intracellular bacterial parasite, Listeria monocytogenes. They do so by a cell-mediated immunological mechanism as evidenced by the protective immunity transferred adoptively by thoracic duct lymphocytes or peritoneal exudate cells from donors infected with this organism. But peritoneal exudate cells from thymus-derived donors convey only a fraction of the immunity transmitted by exudate cells from similarly infected intact rats. Since thymectomized irradiated animals can mobilize their cellular defenses more effectively when they are injected with a modest number of thoracic duct lymphocytes, an effect that cannot be duplicated with a massive infusion of bone marrow, it is argued that thymusdependent lymphocytes or T cells have an influential role in the development of cellular resistance to infection.

RECENT YEARS have witnessed the emergence of Listeria monocytogenes among the pathogenic bacteria into an exciting organism. It seems to be everywhere, yet when the bacteriologist reaches out to isolate it, it often eludes his culture. And so its proper place in human and veterinary medicine remains a riddle, but with an increased awareness of the disease stimulated by the ever-mounting number of case reports, it may eventually be found to be of greater importance than previously suspected. Following this development the organism attracted the attention of numerous investigators who no longer saw a neglected and often ignored bacterium but rather a potential menace,. a bacterium with little regard for host species or geographical distribution, an indiscriminate killer of young and old alike, a bacterium that warranted a complete study to determine effective methods of diagnosis, methods of treatment, and a system of control. Considerable progress has been made toward attaining some of these goals. Others are as distant as they were when Murray, et al.,49 first described the bacterium in 1926, or when Nyfeldt53 in 1929 showed that it could be a cause of disease in man, or when Gill20 in 1933 showed that it could also attack domesticated animals. Unfortunately its epidemiology must be listed among the latter group. At present no intelligent estimate can be made of the actual incidence of listeric infection, but recent evidence suggests that it is not as rare as once suspected; merely rarely recognized. It occurs on all continents except Antarctica and ranges from the Arctic Circle to Australia, South Africa, and Argentina. In addition to man the bacterium attacks or may be harbored 4by at least 35 mammals and 17 fowl, including domesticated animals, house pets, zoo, laboratory and feral animals.29'69 It has been isolated from ticks,41'44'55 pond reared trout,74 crustaceans,71 stream water,56 mud,9 sewage,34 and silage.28 This broad distribution presents a peculiar paradox: At one and the same time L. monocytogenes apparently is distributed widely in nature, yet the sporadic occurrence of the disease suggests that its distribution is actually restricted; or that the bacterium is pathogenic and recognizable only under limited, specific conditions; or that it is overlooked; or that its presence cannot be detected by existing culture methods. Much unfinished work re

Meningitis caused by Listeria monocytogenes occurs predominantly in the neonate and the aged. It is the most common manifestation of listeriosis in humans. Although listeriosis is recognized as a major global problem in both human and animal health, the epidemiology of human infection is poorly understood; attention presently centers about events of pregnancy and the puerperium. Animals and animal products may represent reservoirs for human infection. Thirteen instances of meningitis caused by this organism are reported; death occurred in only one infant. Antimicrobial therapy resulted in recovery without evident sequelae in the remaining 12 patients.

Four drugs, representing four different categories of cytotoxic agents, were studied for their effect on the immune response to Listeria infection in mice. The development of the host's immune response is revealed by a progressive change in the slope of the bacterial growth curve in spleen and liver. It has its onset at 24 hr in untreated mice, but in the presence of effective immunosuppression the organism multiples uninterruptedly until the animal dies from overwhelming infection. When administered as single injections at the time of infection, cyclophosphamide, vinblastine, and azathioprine all produced an effective immunosuppression, characterized by continuous bacterial multiplication. Methotrexate was also immunosuppressive, but unlike the others its effects were reversible. They could be sustained, however, by further treatment. Studies of the time-response relationship indicated that cyclophosphamide was highly active over a broad time-span ranging from 2 days before infection to 4 days after infection. Vinblastine on the other hand was maximally active when given on the day of infection, while methotrexate had its greatest effect when given 48 hr after infection. These differences indicate that these three drugs act on different cell populations involved in the host's immune response. The effects observed have been discussed in relation to what is known of the modes of action of the drugs tested. An observation of interest was the phenomenon of enhanced immunity in animals treated with cyclophosphamide or vinblastine 7–11 days before, and with methotrexate 4 days before infection; reactive hyperplasia of lymphoid tissue following withdrawal of drug was again advanced as an explanation for the occurrence of this paradoxical effect. The experimental model employed is simple, requiring only routine bacteriological facilities and minimal equipment. It seems to offer a useful means of assessing the immunosuppressive activity of drugs and of determining the time-course of their action; it could also be of value in the screening of anticancer agents.

Silverman, Sidney J. (U.S. Army Biological Laboratories, Fort Detrick, Frederick, Md.), Lynn P. Elwell, and James F. Drawdy . Influence of route of infection and other factors on growth and distribution of Listeria monocytogenes in organs of mice. J. Bacteriol. 86: 355–362. 1963.—The growth of Listeria monocytogenes in the lungs, liver, spleen, brain, and blood of mice was observed after infection by the respiratory, intravenous, and intraperitoneal routes. The lungs of mice exposed to Listeria aerosols contained about 10 6 infected cells per ml within 24 hr, and the number of organisms remained high for at least 9 days. After exposure by the other two routes, fewer organisms appeared in the lungs. The colony counts of organisms in spleen and liver homogenates were similar regardless of the route. Organisms were found sporadically in the brain and blood. When a cell extract of Listeria was injected simultaneously with the organisms, greater numbers of Listeria were found in spleen and liver than when the bacteria were injected alone. On the other hand, the BCG strain of Mycobacterium tuberculosis enhanced the resistance of the mice, as shown by the recovery of fewer organisms from tissues when compared with tissues from mice receiving L. monocytogenes alone. Prior administration of BCG also reversed the effect of the Listeria extract. Mice (5 to 6 weeks old) born of Listeria -infected mothers were infected with the homologous organism by the intraperitoneal route. Fewer organisms were recovered and the gross pathology was less extensive than in infected progeny of healthy females. However, there was no difference in the lt 50 (time to death for 50% of the animals) between the two groups. In a similar experiment, using 7- to 8-week-old mice born of infected and healthy mothers, there was no difference in the bacterial counts, gross pathology, or lt 50 between the two groups.

Summary A case of septicemia in the neonatal period due to Listeria monocytogenes is reported. The pathologic anatomy is described and the literature on this subject is reviewed. The epidemiology is discussed. Bacteriological diagnosis is emphasized and specific treatment is presented.

Meningitis duetoErysipelothrix monocytogenes (Listeria monocytogenes, Pirie) isgenerally considered tobeararedisease. Kaplan (1945), who reviewed theliterature, collected records of 14 proved casesofmeningitis duetothisorganism. Since thenatleast 14others havebeendescribed, chiefly intheAmerican literature. Murray (1955) believes, however, thathumaninfection withEry. monocytogenes isprobably morecommon thanis realized. Hepoints outthatGermanpapers alone list some150described casesofmeningitis and meningo-encephalitis, granulomatosis infantiseptica, septicaemia, andmononucleosis causedbythis organism. Murray estimates thatmeningitis and meningo-encephalitis comprise roughly 330% ofall published cases. Inthis country only twocasesofmeningitis have beenreported. Gibson(1935) described afatal case ina37-year-old labourer caused bya diphtheroid organism thatwaslater identified byWebband Barber (1937) asListerella inonocytogenes. In1938 Wright andMacgregor (1939) cultivated theorganism fromthecerebrospinal fluid ofa 17-month-old boydying ontheseventh dayofillness. Thepurpose ofthispaperistoreport twoapparently unconnected cases ofmeningitis duetoEry. monocytogenes occurring inLeicestershire within thespace ofeight weeks, andtofocus attention ontheexistence ofa disease that maybemorecommoninthis country thantheliterature indicates. CaseRecords

Listeria (Listerella) monocytogenes is a rare causative agent of meningitis in man. It is a natural pathogen for rabbits, causing a disease characterized by an excess of mononuclear leukocytes in the blood. Since its first isolation from rabbits by Murray, Webb and Swann in 1924, it has been recovered from human and from other animal sources. I t has been cultured from blood and spinal fluid of patients with syndromes resembling infectious mononucleosis (Nyfeldt, Pons and Julianelle and Webb). Human meningo-encephalitis due to L. monocytogenes was first described by Burns in 1936. Since then, 23 cases of meningitis have been reported in which the organism was identified, and 9 in which the most probable diagnosis was listerellosis.

Mice injected with 50–150 μg of Concanavalin A, intravenously, showed increased resistance to infection by Listeria monocytogenes. The number of organisms that lodged initially in the spleen was the same in both untreated and treated mice; yet the subsequent bacterial growth in the treated group of mice was reduced by 10 to 100-fold. The increased resistance to Listeria infection was not seen in thymectomized mice. The treated mice did not show an enhanced specific immunity to Listeria as compared to the untreated mice. In contrast, Concanavalin A enhanced the immune response to hemocyanin but only when administered a day before with it. We conclude that the resistance to listeriosis was brought about by nonspecific stimulation of T lymphocytes by Concanavalin A.

Ampicillin was efficacious in the treatment of two patients with meningitis due to Listeria monocytogenes. The use of intrathecal ampicillin for this infection is described, we believe, for the first time. Ampicillin may well be the drug of choice in the treatment of listeria infection.

L. monocytogenes is a significant cause of perinatal loss in animals. Neonatal death and a wide spectrum of disease in all age groups can occur in man following infection with the organism. In the past decade listeriosis has been suspected of being an important cause of fetal loss, although the majority of recent reports have not substantiated this. We were unable to isolate L. monocytogenes from any of 76 patients with current fetal loss in a prospective study. Cultures were obtained from vaginal cervical swab, umbilical cord, meconium, and placenta. Six other patients who had meningitis with overt listeriosis were observed during the course of this study.

The resistance developed by mice during infection with Listeria monocytogenes, Brucella abortus, or Mycobacterium tuberculosis is not specifically directed against the infecting organism. The processes involved in the induction of acquired resistance, however, are highly specific and seem to depend upon two factors: a state of immunological reactivity of the host and the presence of the specific microbial antigens to which the host has become reactive. When these two coexist in the tissues the host is found to be non-specifically resistant. It is suggested that resistance, which was shown to depend upon an altered state of host macrophages, may be due to the interaction of antigen and a specific antibody adsorbed to the surface of host macrophages; and that the antibody involved in the reaction is perhaps identical with the antibody which confers the state of delayed-type hypersensitivity. The results are discussed in relation to the question of latent infection and infection immunity.

Infection with Listeria monocytogenes results over the first 6 days in a massive increase in the replication of pyroninophilic cells in the red pulp of the spleen. The production of these cells is associated with increased cellularity of the red pulp and with the development of delayed hypersensitivity. This acquired lymphoid cell population can be eliminated from the spleen at any time by a 2.5-mg dose of cortisone acetate. The capacity of the spleens of infected donor mice to transfer adoptive antimicrobial immunity to normal recipients depends on the size of the acquired, lymphoid cell population in the red pulp. If this cell population is allowed to decline naturally, or is eliminated artificially by cortisone acetate, the spleen also loses cells capable of transferring immunity to normal mice. It is concluded, therefore, that the increased cellular division in the red pulp during infection represents in part the production of immunologically committed lymphocytes. These cells are short-lived and cortisone-sensitive, and they are distinguished from immunocompetent cells which are long-lived and cortisone-resistant. An infusion of committed lymphoid cells protects cortisone-treated recipients from Listeria infection. This is evidence that cortisone does not have an important effect on the hosts' macrophage system, but that its infection-enhancing effect is due primarily to its action on committed lymphocytes.