Charles L. Wisseman

The acquisition of Rickettsia tsutsugamushi by chiggers (trombiculid mites) during the feeding process.

A fundamental concept in the ecology of ectoparasite-borne disease is that of the reservoir, or the wellspring of the infection in nature during interepidemic periods. In the case of chigger-borne rickettsiosis (scrub typhus), it has often been argued that chiggers (larval trombiculid mites) are not only the vectors but also the true reservoirs of the infection and that the small mammals (theraphions) that serve as hosts of the chiggers are of no importance as a source of rickettsiae for the chiggers.’ This point of view has been based largely upon several factors, namely, the known transovarian transmission of the causative agent, Rickettsia tsutsugamushi. from mother to progeny in certain species of chiggers,’ the demonstration of the efficiency of the mechanism of transovarian transmission by Rapmund and his colleagues,+-” the difficulty or impossibility to show that chiggers can acquire R . tsutsugamushi while feeding on infected hosts in the laboratory,’. c l l the fact that chiggers are unique among vectors in that in their lifetime, they are parasitic only in one stage (i.e., as larvae) and normally attach to, and feed upon, only one vertebrate and therefore could not acquire an infection from one such host and transmit it later directly to a second, and, finally, the widespread belief that chiggers do not imbibe blood but, instead, feed solely on serum exudate when in the parasitic stage and thus are unlikely to come in contact with pathogens that circulate in the blood of the host.‘, In the present paper, it is shown that, contrary to general belief, chiggers can acquire R . tsutsugarnushi while feeding on rickettsemic mice and that, when tested by pools of chiggers, this acquisition is relatively frequent. Persistence of acquired rickettsiae for at least 1-2 weeks in the chiggers is demonstrated, and a single case of presumed transovarian transmission to the next generation is reported. The preliminary data presented suggest, somewhat surprisingly, that in nature, under certain conditions, a small but perhaps significant proportion of chiggers may partially feed on one host and then later feed to repletion on a second one, raising the possibility that such “reattached” chiggers may

Inhibition of Adaptive Enzyme Formation by Antimicrobial Agents

Summary Chloramphenicol, aureomycin, terramycin and nitroacridine 3582 inhibit the formation of certain adaptive enzymes in E. coli. This effect per se is not responsible for the bacteriostatic activity of these substances, but it probably points toward a general interference with protein metabolism of the organism.

TREATMENT OF TYPHOID FEVER WITH ANTIBIOTICS

Today, typhoid fever has become much less conspicuous in many parts of the world, largely because of the expansion of sanitary facilities and organized preventive medicine. Nevertheless, cases continue to occur even in the United States and require adequate therapy. Many of the chemotherapeutic and antibiotic agents possess significant inhibitory action on Salmonella typhosa when tested i n vitro. Despite these laboratory promises, only chloramphenicol has proved of value in the treatment of patients with this disease.’ Even some of the antibiotics, which appeared to be more promising than chloramphenicol in laboratory studies, have proved decidedly inferior for the care of patients; viz., penicillin, streptomycin, aureomycin, polymixin, and terramy~in.~-’ Despite the obvious benefits of chloramphenicol therapy in typhoid fever, several important problems remain unsolved. These are: (1) relapses of typhoid fever occur in an appreciable proportion of treated patients; ( 2 ) S. typhosa are shed in the feces for variable periods after institution of therapy; (3) when present, the typhoid-carrier state is not permanently benefited by chloramphenicol or other antibiotics; and (4) the two common complications, perforation of and hemorrhage from the intestinal ulcer, continue to occur. At least, the first three of these problems are concerned with the fact that chloramphenicol is primarily bacteriostatic rather than bactericidal, in the human body. This report is concerned with a review of the therapeutic effects of chloramphenicol in typhoid fever, and the limitation of this form of treatment. The incidence of common complications, their management, and possible ancillary therapeutic measures are also discussed. Eject on Toxemia and Febrile Course. The course of the toxemia and pyrexia in typhoid fever is notably variable, but the usual total duration in uncomplicated adult cases, who receive only supportive therapy, ranges between 30 and 40 days. Although toxemia and pyrexmia are not inseparable in untreated or treated cases, they generally go hand in hand during the course of the disease. An analysis of 58 patients, carefully studied by our group5# 8 s and summarized in TABLE 1, reveals that, irrespective of age, severity of illness, or stage of disease, when specific therapy was first instituted, the temperature returned to normal levels in an average of 4.0 days. Numerous investigators have noted the uniform consistency of this three to five day febrile toxic course in some several hundred treated cases.6* 6 * 8-12 FIGURE’ 1 summarizes the findings in a representative case of typhoid fever treated with chloramphenicol. Incidentally, this patient was a member of the original group in which chloramphenicol was first shown to be efficacious in typhoid fever. This 15-year-old boy was started on therapy on the seventh

Concepts of Louse-Borne Typhus Control in Developing Countries: The Use of the Living Attenuated E Strain Typhus Vaccine in Epidemic and Endemic Situations

Louse-borne or epidemic typhus fever is without doubt one of the great epidemic diseases of mankind whose ebb and flow through the centuries has been important in the molding of human destiny (1). Much of our knowledge about typhus fever has come from experience in the unique setting of the temperate north of Europe (1–16) where its relative importance has declined as living conditions have improved over many years. Indeed, in recent times the epidemic potential of typhus in Europe has been realized primarily in the wake of the catastrophic disruptions caused by wars. Our attitude about relative importance, epidemiology, approaches to control and level of research support has been influenced strongly by the trends in modern, advanced Europe.

The Effect of Hyperthermia on Dengue Virus Infection of Mice

Summary Passively induced hyperthermia significantly delayed or prevented lethal CNS infections of mice produced by a line of type 1 dengue virus with a history of 33 serial mouse brain passages (MP-33) but not one with a history of 125 passages (MP-125). This effect was not due to any enhancement of interferon production in the brain but was the result of a reduced rate of viral multiplication. Permanent recovery from MP-33 infection in hyperthermic animals was correlated with the appearance of the immune response.

The Presence of Diaminopimelic Acid in the Rickettsiae.

Summary Diaminopimelic acid is present in whole cells of R. prowazekii, R. mooseri, R. quintana, and C. burneti in concentrations only slightly lower than those reported for Gram negative bacteria. In each species studied meso DAP is the only isomer present.

MODIFICATION OF ANTITYPHUS ANTIBODIES ON PASSAGE THROUGH THE GUT OF THE HUMAN BODY LOUSE WITH DISCUSSION OF SOME EPIDEMIOLOGIC AND EVOLUTIONARY IMPLICATIONS

Evidence is presented to indicate that proteolytic and perhaps other enzymes of the louse midgut, essential to the nutrition of the louse, perform molecular dissection on the antirickettsial antibodies present in the blood of a typhus-immune host that selectively destroys, along with other functions, the portion of the antibody that determines the only known function by which antirickettsial antibodies may operate in host defense mechanisms, namely, opsonization of rickettsiae for enhanced ingestion by professional phagocytes and subsequent destruction. The epidemiologic significance of these findings is discussed in relation to the progressive destruction of cells that produce digestive enzymes of the louse midgut that occurs with progressive rickettsial infection, and the possibility of a negative feedback mechanism in transmission is introduced. Speculations that involve evolutionary concepts of both convergent and divergent varieties with respect to rickettsiae, potentially operational in a system that consists of an obligate blood-sucking arthropod vector and a vertebrate host capable of adaptive responses to both vector and rickettsial agent, are presented.

Complement Fixing Antibody Response of Man to Yolk Sac-Grown Rocky Mountain Spotted Fever Vaccine∗

Summary and Conclusions The spotted fever group complement fixing antibody response was used as a measure of the immunogenicity of a commercially available killed Rocky Mountain spotted fever vaccine in human subjects. A single-dose primary course of vaccine elicited a detectable antibody response in only about 22% of 68 subjects, whereas a 3-dose primary course stimulated the development of complement fixing antibodies in about 63% of eight subjects. The low antibody titers attained may be a function of the relatively low complement fixing antigen content of the vaccine. A booster dose of vaccine given between 1 and 6 months after the primary course failed to elicit an antibody response in the majority of subjects. A second booster dose, given a year after the 6-month booster dose, also failed to cause a significant response. On the other hand, three subjects who had last received RMSF vaccine several years prior to this study developed a typical secondary antibody response upon revaccination. These same subjects, however, failed to show an antibody response to an additional dose of vaccine 6 months later. The interval between doses or courses of the currently available vaccine required for eliciting an optimal secondary CF antibody response is unknown, but the results of this study suggest that it may be greater than one year. It is unknown if the uniformly low CF antibody response in man to the commercial RMSF vaccine reflects an equally low degree of protection afforded against the disease. Minimum requirements for potency of RMSF vaccine lots released for distribution include demonstration of capacity to protect guinea pigs against challenge with virulent organisms (5). Studies of the protective effect of the vaccine in man would seem desirable to evaluate its efficacy and to establish the degree of correlation of protection with laboratory tests.

An Unusually High Divalent Cation Requirement for Attachment of West Nile Virus to Primary Chick Embryo Cells

Summary An unusually high divalent cation requirement for maximal plaque count and maximal adsorption rate was found in the WNV-CE cell system. An increase in Mg2+ concentration from 1 − 10-3 to 1 − 10-1 M resulted in a 200-fold increase in average plaque count. When 1 − 10-1 M Mg2+ was incorporated in the virus inoculum, WNV attachment was essentially complete in 50-60 min. If 1 − 10-2 M or less Mg2+ was included in the adsorption diluent, maximal attachment was not complete within 300 min and only a fraction of the original virus content could be detected by plaque assay.

Plaque Assay for Rickettsia mooseri in Tissue Samples

Summary A plaque assay using primary CE fibroblasts was shown to be sensitive for the direct isolation and quantitation of the relative number of R. mooseri from infected guinea pig tissues. The authors gratefully acknowledge the advice and assistance of Paul Fiset, A. D. Waddell, and M. Schneider.