Tick-borne rickettsioses are close relatives of typhus

Vera Rahr, Yana Igolkina, Nina Tikunova, Valentin Vlasov “Science at First Hand” No. 1–2(91), 2021

If you are unlucky enough to fall prey to a blood-sucking tick, you risk contracting rickettsiosis, one of many tick-borne infections. The most famous among them are tick-borne encephalitis and borreliosis, while the danger of infection with other pathogens, such as rickettsia, is clearly underestimated. However, these relatives of typhus pathogens are far from harmless, and in terms of occurrence, rickettsioses rank second among bacterial tick-borne infections in the Asian part of our country. Fortunately for us, in Russia, unlike North America and Europe, deaths from rickettsia infection are rare. Nevertheless, tick-borne rickettsioses can occur in severe and sometimes atypical forms; they require hospitalization and adequate treatment.

About the authors

At the end of the 19th century. Among settlers in the foothills of the Rocky Mountains of Montana (USA), a large-scale outbreak of an unknown disease broke out, with high fever, hemorrhagic rash and other severe symptoms - the mortality rate among patients reached 20–30%. In the first decade of the last century, pathologist and one of the first American infectious disease specialists, Howard Ricketts, established that human infection occurs as a result of the suction of blood-sucking ixodid ticks

genus
Dermacentor
. He discovered small bacteria-like microorganisms in the blood of patients and experimentally proved on guinea pigs and monkeys that the infection can be transmitted through contaminated blood.

Female ixodid tick Dermacentor andersoni

- a known carrier of Rocky Mountain spotted fever. © CDC, photo by J. Gathany

Howard (Howard) Taylor Ricketts - American pathologist and microbiologist, discoverer of tick-borne rickettsial diseases. Died in 1910 from typhus, having become infected while studying this disease during an epidemic in Mexico

The causative agent of Rocky Mountain fever is named Rickettsia rickettsii.

in honor of its discoverer, Howard Ricketts. His name is also immortalized in the names of higher taxa - family and order.

For the first time, the term “rickettsia” was used in relation to the causative agent of typhus by Enrique Rocha Lima, head of the pathology department of the Tropical Institute in Hamburg. This pathogen was identified in the body and feces of lice in 1913 by his colleague and friend, the Czech microbiologist Stanislav von Provacek. In 1915, they worked together in the camp hospital in Khotebuz, where a typhus epidemic broke out among Russian prisoners. Provacek became infected and, despite good care and a passionate desire to overcome the disease, died. When Rocha Lima later described the causative agent of typhus, he named it Rickettsia prowazekii

in honor of two researchers who died while studying this dangerous disease. By the way, the participation of lice in the transmission of typhus was first suggested back in 1908 by the domestic scientist Nikolai Fedorovich Gamaleya, and a year later it was experimentally confirmed by the Frenchman Charles Nicolas, who received the Nobel Prize for this discovery.

The disease was called Rocky Mountain spotted fever.

, although it later turned out that it is found throughout almost the entire territory of North America and part of South America.
Ricketts himself in 1910 began studying an unknown disease in Mexico, which turned out to be typhus
, and discovered similarities in both the symptoms and pathogens of this disease and tick-borne fever. While conducting research, a 39-year-old professor contracted typhus and died.

In 1916, the term “rickettsia” was first used by the Brazilian microbiologist and infectious disease specialist Enrique Rocha Lima, the founder of the doctrine of rickettsiosis. Over time, this name was assigned to the entire group of similar microorganisms, which includes the causative agents of both tick-borne spotted fevers and typhus fevers, transmitted by lice and fleas.

This historic photo from 1953 shows technicians at the CDC's Virus and Rickettsia Laboratory studying Rocky Mountain spotted fever. As you can see, personal protective equipment (PPE) of that time consisted of a regular lab coat and a cloth headgear. © CDC

In Russia, the first cases of tick-borne rickettsiosis were noted in 1934–1936. in the territories of the Krasnoyarsk Territory and the Far East - approximately at the same time when spring outbreaks of tick-borne encephalitis

. This was a time of active development of the eastern regions of the country, so epidemics of unknown diseases attracted special attention.

Later, scientific expeditions managed to accurately establish the nature of the infection and isolate its causative agent, named Dermacentor oxenus sibirica

(later
Rickettsia sibirica
).
The disease itself was called North Asian tick-borne rickettsiosis
, or
Siberian tick-borne typhus
(Loban, 2002).

This disease is tied to certain areas - natural foci

. In our country, they are found in Siberia and the Far East, as well as in neighboring countries - Turkmenistan, Armenia, Kazakhstan and Mongolia. At the same time, the role of vertebrates as a reservoir of infection is apparently insignificant. In practice, rickettsiae are very rarely detected in the same rodents, unlike the causative agents of other diseases transmitted by ticks. As for a person, he, as in the case of other tick-borne infections, becomes only an accidental victim as a result of the bite of an infected tick.

A child's hand covered with a papular rash characteristic of Rocky Mountain spotted fever, the most severe and most commonly reported rickettsiosis in the United States. © CDC

Typhus - epidemic and endemic

The group of typhus includes the causative agents of epidemic (louse-borne) typhus - Rickettsia prowazekii
, and endemic (flea, rat) typhus -
Rickettsia typhi
.

Epidemic typhus is characterized by a cyclical course with fever, rash, and acute damage to the nervous and cardiovascular systems. Its source is always a sick person, and the carrier is a body or head louse. Humans are infected by rubbing lice feces into the skin during scratching or through the mucous membranes of the eyes and respiratory tract (Rudakov et al., 2016). The infection is not transmitted through lice bites, since the pathogen multiplies only in the epithelial cells of the insects' intestines (Loban et al., 2002).

Endemic typhus is characterized by a cyclical course with the appearance of a roseolous-papular rash on the skin; The course is mostly benign and the mortality rate is low. The reservoirs of infection are rats and house mice, and the carriers are fleas, three types of lice and several types of gamasid mites. Transmission to humans occurs through the fecal-inhalation-contact route (Loban et al., 2002). It is found on all continents except Antarctica.

Bacterial “relatives” of mitochondria

Rickettsia are one of the smallest bacteria: their length does not exceed 1–2 microns, which is comparable to the size of large viruses; In addition, they are unable to grow on nutrient media. This is not surprising: these bacteria are exclusively intracellular parasites and can reproduce only in the cells of living organisms.

Due to the small size of rickettsiae, they are difficult to see in tissue using conventional histological methods. To detect the presence of Rickettsia rickettsii

In this sample of yolk sac tissue from developing chick embryos (they are used to cultivate these bacteria), a special Gimenez staining method was used. Fuchsin in an aqueous solution with phenol and ethanol colored the rickettsia crimson, and malachite green gave contrast to the tissues. Photo 1974 © CDC

The tendency of rickettsiae to live a comfortable and safe life is in good agreement with the opinion that these bacteria are evolutionarily closest to extinct microorganisms that became the progenitors of the most important intracellular organelles - mitochondria

. These structures are engaged in the production of ATP molecules, a universal source of energy for cells. Mitochondria have their own genome, which is passed on through a series of generations (including in humans) along the maternal line.

Currently the genus Rickettsia

unites more than 40 species, which are divided into several groups and subgroups.
Types of rickettsia pathogenic to humans are included in two main groups: typhus
(carriers are lice and fleas) and
tick-borne spotted fevers
(carriers are ticks, respectively). As for the remaining groups, their danger to humans remains to be studied.

The genomes of most known rickettsia species, represented by a single circular chromosome, have already been deciphered. Compared to free-living bacteria, they are small, which is, in principle, characteristic of intracellular parasites - why have a large genome when you already live on everything ready-made? Because of this, genomic rearrangements are rare in rickettsiae, since with such a size any changes can have disastrous consequences.

But even of this small number of rickettsia genes, some were borrowed by them from other organisms. For example, in the genome of R. felis

there are more than one and a half hundred genes that came to them from other bacteria and even higher organisms (
eukaryotes
).

The loss of some regulatory genes can change the pathogenicity of a bacterium, in any direction. For example, the genome of one of the most pathogenic rickettsiae - R. prowazekii

, the smallest. But rickettsia may also lose genes that make it pathogenic.

The genome of some rickettsia also contains plasmids

- free genetic elements that can be inherited relatively independently and even transmitted from one bacterium to another during
conjugation
(a bacterial analogue of the sexual process). But little is known about their role in the life of rickettsiae.

#4. Other diseases that occur after a tick bite

The above diseases do not complete the list of all diseases that are transmitted by a tick bite. In addition to them, there are numerous fevers :

• Omsk hemorrhagic fever
• West Nile fever
• Q fever
• Crimean-Congo hemorrhagic fever
• Marseilles fever and others

All of them are found on the territory of Russia in certain areas where ticks live. In addition, there is a disease called babesiosis. It is also transmissible, i.e. transmitted by the bite of blood-sucking insects. Several specific diseases also occur in animals . For example, theileriosis, various types of rickettsiosis and others.

Thus, the list of diseases that can be contracted from a tick bite is quite extensive. Therefore, when attacked by a parasite, you need to be vigilant and be attentive to the state of the body after the bloodsucker attack . So be extremely careful and take care of your health!

Useful articles about ticks:

– How do ixodid ticks attack?

– Do I need to be vaccinated against ticks?

– Features of ixodid ticks: what do you need to know?

Ab ovo

Of the 36 species of rickettsia belonging to the tick-borne spotted fever group, only 16 are dangerous to humans. Transmission of tick-borne rickettsiosis occurs as a result of the suction of an infected tick. The exception is the species R. felis

, which is carried by fleas. In cats it causes a febrile state, and in humans it causes symptoms quite typical for rickettsial infections; neurological disorders are also possible.

Images of morphological structures of the American dog tick ( Dermacentor variabilis

), one of the vectors
of R. rickettsii
: details of the mouth opening, dorsal sensory hair, leg appendages. Scanning electron microscopy. © CDC, photo JH Carr

In the body of the tick itself, rickettsia can be found almost everywhere, including the salivary glands and ovaries. Therefore, they can not only remain in an individual throughout its entire life, from the larva to the imago ( adult)

), but also, through the egg, is very effectively transmitted to the offspring (Rudakov et al., 2016). And this is how rickettsia differs from other infectious agents, such as tick-borne encephalitis virus or Borrelia.

Due to the transmission of the pathogen between generations, the infection rate of some species of ixodid ticks can reach 70–80%! Therefore, the suction of both adult ticks and larvae and nymphs poses a danger to humans. The larvae are especially likely to attack children and can go undetected due to their small size, making it difficult to diagnose when infested.

Certain types of rickettsia “gravitate” towards “their” types of ticks - knowledge of these characteristics helps to assess the epidemic situation in different territories.

Thus, in the Asian part of the Russian Federation, the most common species found in ticks is Candidatus R. tarasevichiae

,
R. raoultii
,
R. helvetica
,
R. sibirica
and
R. heilongjiangensis
(the last two pose the greatest danger to humans).
At the same time, for example, the species R. raoultii
and
R. sibirica
clearly prefer ticks of the genus
Dermacentor
(Igolkina et al., 2018a; Medianikov et al., 2006; Shpynov et al., 2006).

The geography of tick habitat also makes unexpected adjustments. Candidatus R. tarasevichiae is most often detected in taiga ticks

, on Sakhalin more than 60% of these ticks are infected with a completely different rickettsia -
R. helvetica
. This difference is likely due to the geographical isolation of the island.

Epidemics of typhus that broke out during wars claimed the lives of millions of people - the mortality rate reached 10%.
An example is the catastrophic situation that developed during the Civil War in Russia. Thus, in Novonikolaevsk (modern Novosibirsk) in the terrible epidemic of typhus that broke out in the winter of 1919–1920, over 60 thousand Red Army soldiers and local residents died. As they wrote in the report to the meeting of the Tomsk Gubernia Revolutionary Committee: “The overall picture is not an epidemic, but a pestilence. The goal and efforts of Gubchekatif are to turn the pestilence into an epidemic.” Typhoid epidemics in the city stopped only in 1922–1923. In the Russian Federation, the last outbreak of typhus was registered in 1998 in a psychoneurological hospital in the Lipetsk region. Currently, foci of infection continue to exist in countries with low living standards in South and Central America and Africa.

#2. Tularemia

Another fairly common disease in Russia and other countries, transmitted by a tick bite. At the same time, attacks by infected arthropods are not the only way of transmitting the disease . It can be distributed:

• in direct contact with sick animals (living or dead),
• through contaminated food and water,
• and also through inhalation of air containing pathogenic organisms.

Tularemia is caused by the bacteria Francisella tularensis. These microorganisms can live not only inside living organisms. They quite successfully maintain their viability on vegetation, straw, and grain .

Development of tularemia

The incidence of illness when bacteria enter the body is very high . Almost no one avoids developing the disease after the tularemia bacillus enters the body. The hidden period can last up to 30 days . However, most often within a week after a tick bite, tularemia makes itself felt.

The symptoms of the disease are as follows (many of them are similar to those of tick-borne typhus):

Lymph node involvement

• sudden increase in temperature, fever;
• intoxication, loss of strength;
• pain in the body and head;
• extensive inflammation of the mucous membranes;
• rash;
• slow heart rate,
• lowering blood pressure,
• enlarged liver and spleen.

The lymph nodes are very affected . They swell and suppurate, forming so-called buboes. Some can reach up to 5 cm in diameter. Other signs of the disease may vary greatly depending on the type and source of infection.

Treatment and prevention of tularemia

Therapy is carried out with antibiotics, both specific and broad-spectrum. Additionally, intravenous detoxification procedures are carried out to relieve and alleviate the state of intoxication of the body. When the lymph nodes suppurate, they are opened and cleaned. If necessary, antipyretic drugs, vitamin supplements and other medications are used.

To prevent the development of tularemia, I often use vaccination . The vaccine is valid for five years or more. Therefore, it is often used in areas with an increased risk of transmission of tularemia bacilli due to a tick bite or contact with other sources of infection.

Astrakhan, Siberian, Far Eastern

Most rickettsial infections have the same typical symptoms: high fever and blotchy rashes on the skin, as well as swollen lymph nodes near the bite site. At the site of tick suction there is often a sore covered with a dark crust and surrounded by an area of ​​reddened, inflamed skin. Muscle and headaches, lethargy, apathy, sleep disturbances, and in rare cases, neurological disorders may occur.

Forest tick ( Dermacentor andersoni)

) on the man's back. Note the unusually strong local reaction in the form of redness of the skin and inflammation at the site of the bite. © CDC/NIAID

At the same time, rickettsioses caused by different pathogens may have characteristic features and differ in the severity of the disease. One of the most severe is Rocky Mountain spotted fever: even with timely treatment, the mortality rate reaches 4%. Mediterranean spotted fever is widespread in Europe

with a mortality rate of up to 2.5%.

“Domestic” rickettsioses, fortunately, have a milder course. Officially, only two types of tick-borne rickettsioses are registered in the Russian Federation: in the European part (mainly the Astrakhan region) Astrakhan spotted fever

(20 cases per 100 thousand population) (Rudakov, 2016), in the Asian part - the already mentioned Siberian tick-borne typhus. The most cases of the disease outside the Urals were registered in the Altai Territory, as well as in the Altai Republic (up to 130 cases per 100 thousand population).

But although it is believed that in the Asian part of Russia there is only one tick-borne rickettsiosis, which is caused by R. sibirica

, it was recently found that in the Khabarovsk Territory the pathogen most often is the species
R. heilongjiangensis
(Mediannikov et al., 2006).
The disease even got its own name: Far Eastern tick-borne rickettsiosis
.

The causative agents of rickettsiosis can only be distinguished using molecular genetic methods. Thus, it was shown that R. sibirica

indeed, it is the main infectious agent in the Novosibirsk region and Altai (Igolkina et al., 2018b; Granitov et al., 2015), but the remaining territories of Western and Eastern Siberia in this sense remain unstudied.

Genus Rickettsia

belongs to the family Rickettsiaceae, which also includes the genus
Orientia
.
The bacterium Orientia tsutsugamushi
is the causative agent of Tsutsugamushi fever (Japanese river fever), which proceeds according to a scenario typical of all rickettsial diseases: with fever, skin rashes, etc. It is transmitted by the larvae of red-celled mites.
The photo shows
a bacterial cell
O. tsutsugamushi
being engulfed by a mouse peritoneal mesothelial cell. Transmission electron microscopy. Photo 1976 © CDC

Since even in Russia the fatal outcome of rickettsiosis is not excluded, the disease must be promptly recognized and treated. The diagnosis is now made by characteristic clinical manifestations, and tetracycline

(eg
doxycycline
).
Rickettsia are also sensitive to chloramphenicol
(
chloramphenicol
) (Rudakov, 2016). Those who have recovered from the disease develop strong immunity to all tick-borne rickettsioses, regardless of the pathogen. No relapses are observed.

But here, too, not everything is so smooth.

Atypical infections

Recently, in different countries, in addition to the well-studied “typical” tick-borne rickettsioses, cases with uncharacteristic symptoms have been reported, the causative agents of which were previously considered non-pathogenic (for example, R. raoultii

,
Candidatus R. tarasevichiae
,
R. helvetica
).

As for our country, DNA analysis of clinical samples from patients with typical and atypical symptoms from the Novosibirsk region and Altai revealed that all people bitten by the “Altai” tick were infected with the same pathogen R. sibirica

(with one exception).

But Novosibirsk residents were infected with a whole “bouquet” of different rickettsia. Among them were the species R. raoultii

,
R. aeschlimannii
and
R. slovaca
- such infections were noted on the territory of the Russian Federation for the first time, despite the fact that the latter two pathogens were not previously detected in ticks in the Novosibirsk region. What was most surprising was the fact that the rickettsiae from some patients represented new genetic variants that could not be attributed to known species (Igolkina et al., 2018b).

Rickettsia, which causes Rocky Mountain fever, is found not only in ixodid ticks, but, for example, also in soft ticks Ornithodoros kelleyi
, which parasitize bats. However, today there is no evidence that a person can become infected through the bite of this arthropod. © CDC, photo by J. Gathany

The clinical manifestations of rickettsioses caused by “uncharacteristic” pathogens varied markedly. Thus, patients infected with R. raoultii

, significantly more often had meningeal symptoms, and the most severe forms of the disease were observed in elderly patients, as well as those with immunodeficiency. It is possible that these rickettsioses also occur in other regions of Russia, but they cannot be identified on the basis of symptoms alone.

The difficulty of making a diagnosis in atypical cases is also evidenced by the fact that in Novosibirsk residents infected with R. slovaca

and new genetic variants of rickettsia, symptoms characteristic of rickettsial diseases were not observed.

Regarding Candidatus R. tarasevichiae

, then cases of rickettsiosis caused by this bacterium are rare, despite its frequent occurrence in ticks;
it is possible that it may only cause infection in immunocompromised people. At the same time, one case of the disease was registered in Russia in a child caused by simultaneous infection with two types of rickettsia: Candidatus R. tarasevichiae
and
R. sibirica
. The disease was fatal (Rudakov et al., 2019).

Human infection with tick-borne fevers occurs due to the suction of an infected tick, when rickettsiae enter the body with saliva. The incubation period averages 3–7 days. Bacteria first multiply at the site of the bite (because of this, a crust forms there - the so-called “primary affect”), then they enter the regional lymph nodes (lymphadenitis, lymphadenopathy is formed), then into the blood (Rudakov, 2016). The rash appears on the 2nd–5th day of the disease. Rickettsiae primarily infect endothelial cells (the inner lining) of blood vessels, but can infect liver cells (hepatocytes) and immune cells (macrophages).

Brief historical data

Descriptions of mass diseases occurring with the clinical picture of typhus are found already in the works of doctors of ancient times, then they were reported in works on medicine dating back to the Middle Ages and modern times. The clinical characteristics of diseases that emerged in the first half of the 19th century made it possible in 1856 to establish the nosological independence of typhus and typhoid fever and to distinguish them from an undefined group of fever diseases.

A great contribution to the development of clinical issues and pathology of typhus was made by such outstanding clinicians as S.P. Botkin - in Russia, Liebermeister - in Germany and Murchison - in England. Works by L.V. Popov (1875) proved the existence of specific changes (granulomas) in small vessels of the brain in people who died from typhus. In 1877 O.O. Mochutkovsky in Odessa proved the presence of an infectious factor (pathogen) in the blood of patients with typhus, and a little later G.N. Minkh, based on epidemiological observations, suggested the role of lice in the transmission of this infection. Later, the role of lice in the transmission of infection was proved by the French scientist Charles Nicole (1909). The works of Ricketts (in America) and Provaček (in the Czech Republic) established the most important features of the pathogen (Rickettsia Provaček).

Classical studies (1916-1921) by the prominent Soviet scientist I.V. Davydovsky were completed with a comprehensive description of the pathological anatomy of typhus. Since 1916, the Weil-Felix serological reaction has been used in the laboratory diagnosis of typhus. In 1939, Durand obtained a vaccine for vaccination against typhus. The biological properties of the pathogen, epidemiology, pathogenesis, immunogenesis were studied in detail, the clinic in all its variants was described in detail. Since 1950, antibiotics (synthomycin, chloramphenicol, biomycin, tetracycline) have been successfully used to treat typhus. In Russia, typhus has been eliminated.