Relationship Between Climate Change and Marmot Plague of Marmota himalayana Plague Focus - the Altun Mountains of the Qinghai-Xizang Plateau, China, 2000-2022.

Introduction: Plague is a zoonotic disease that occurs naturally in specific geographic areas. Climate change can influence the populations of the plague host or vector, leading to variations in the occurrence and epidemiology of plague in animals. Methods: In this study, we collected meteorological and plague epidemiological data from the Marmota himalayana plague focus in the Altun Mountains of the Qinghai-Xizang Plateau. The data spanned from 2000 to 2022. We describe the climatic factors and plague epidemic conditions and we describe their analysis by Pearson's correlation. Results: During the period from 2000 to 2022, the isolation rates of Yersinia pestis (Y.pestis) from marmots and fleas were 9.27% (451/4,864) and 7.17% (118/1,646), respectively. Additionally, we observed a positive rate of F1 antibody of 11.25% (443/3,937) in marmots and 18.16% (142/782) in dogs. With regards to climate, there was little variation, and a decreasing trend in blowing-sand days was observed. The temperature in the previous year showed a negative correlation with the Y. pestis isolation rate in marmots (r=-0.555, P=0.011) and the positive rate of F1 antibody in marmots (r=-0.552, P=0.012) in the current year. The average annual precipitation in the previous two years showed a positive correlation with marmot density (r=0.514, P=0.024), while blowing-sand days showed a negative correlation with marmot density (r=-0.701, P=0.001). Furthermore, the average annual precipitation in the previous three years showed a positive correlation with the isolation rate of Y. pestis from marmots (r=0.666, P=0.003), and blowing-sand days showed a negative correlation with marmot density (r=-0.597, P=0.009). Conclusions: The findings of this study indicate that there is a hysteresis effect of climate change on the prevalence of plague. Therefore, monitoring climate conditions can offer significant insights for implementing timely preventive and control measures to combat plague epidemics.

Pasteurella multocida strains of a novel capsular serotype and lethal to Marmota himalayana on Qinghai-Tibet plateau in China.

Pasteurella multocida is a zoonotic pathogen causing serious diseases in humans and animals. Here, we report P. multocida from wildlife on China's Qinghai-Tibet plateau with a novel capsular serotype, forming a single branch on the core-genome phylogenetic tree: four strains isolated from dead Himalayan marmot (Marmota himalayana) and one genome assembled from metagenomic sequencing of a dead Woolly hare (Lepus oiostolus). Four of the strains were identified as subspecies multocida and one was septica. The mouse model showed that the challenge strain killed mice within 24 h at an infectious dose of less than 300 bacteria. The short disease course is comparable to septicemic plague: the host has died before more severe pathological changes could take place. Though pathological changes were relatively mild, cytokine storm was obvious with a significant rise of IL-12p70, IL-6, TNF-αand IL-10 (P < 0.05). Our findings suggested P. multocida is a lethal pathogen for wildlife on Qinghai-Tibet plateau, in addition to Yersinia pestis. Individuals residing within the M. himalayana plague focus are at risk for P. multocida infection, and public health warnings are necessitated.

Alkaloids from Corydalis saxicola and their antiproliferative activity against cancer cells.

Eight undescribed alkaloids named corydalisine D-K (1-7), including one isoquinoline benzopyranone alkaloid (1), one benzocyclopentanone alkaloid (2), four benzofuranone alkaloids (3, 4, and 5a/5b) and two protoberberine alkaloids (6 and 7), along with fourteen known ones, were isolated from the Corydalis saxicola. Their structures, including absolute configurations, were unambiguously identified using spectroscopic techniques, single-crystal X-ray diffraction and electron circular dichroism calculation. Compounds 2, 14 and 21 exhibit antiproliferative activity against five cancer cell lines. The aporphine alkaloid demethylsonodione (compound 14), which exhibited the best activity (IC50 = 3.68 ± 0.25 µM), was subjected to further investigation to determine its mechanism of action against the T24 cell line. The molecular mechanism was related to the arrest of cell cycle S-phase, inhibition of CDK2 expression, accumulation of reactive oxygen species (ROS), induction of cell apoptosis, inhibition of cell migration, and activation of p38 MAPK signaling pathway. The results indicated that 14 could be used as a potential candidate agent for further development of anti-bladder transitional cell carcinoma.

The complex genomic diversity of Yersinia pestis on the long-term plague foci in Qinghai-Tibet plateau.

Plague is a typical natural focus disease that circulates in different ecology of vectors and reservoir hosts. We conducted genomic population and phylogenetic analyses of the Yersinia pestis collected from the 12 natural plague foci in China with more than 20 kinds of hosts and vectors. Different ecological landscapes with specific hosts, vectors, and habitat which shape various niches for Y. pestis. The phylogeographic diversity of Y. pestis in different kinds plague foci in China showed host niches adaptation. Most natural plague foci strains are region-and focus-specific, with one predominant subpopulation; but the isolates from the Qinghai-Tibet plateau harbor a higher genetic diversity than other foci. The Y. pestis from Marmota himalayana plague foci are defined as the ancestors of different populations at the root of the evolutionary tree, suggesting several different evolutionary paths to other foci. It has the largest pan-genome and widest SNP distances with most accessory genes enriched in mobilome functions (prophages, transposons). Geological barriers play an important role in the maintenance of local Y. pestis species and block the introduction of non-native strains. This study provides new insights into the control of plague outbreaks and epidemics, deepened the understanding of the evolutionary history of MHPF (M. himalayana plague focus) in China. The population structure and identify clades among different natural foci of China renewed the space cognition of the plague.

Identification of Novel Bartonella washoensis Sequence Type 22 in Marmota himalayana - Jiuquan City, Gansu Province, China, 2021-2022.

What is already known about this topic?: The prevalence of rodent-adapted Bartonella species has been increasing significantly. However, the specific Bartonella species carried by Marmota himalayana (M. himalayana), a large rodent species, and the potential risk it poses to human populations remain unknown. What is added by this report?: Bartonella washoensis (B. washoensis), associated with human endocarditis, was initially identified in M. himalayana, exhibiting a detection rate of approximately one-third and demonstrating a predilection for the heart and lungs. The discovery of the novel Sequence Type 22 has expanded both the isolation source and genetic lineage of B. washoensis. What are the implications for public health practice?: Individuals residing within the M. himalayana plague focus are at an elevated risk for B. washoensis infection. Consequently, there is a pressing need for public health warnings and efficient clinical case identification in this population.

Serological investigation of plague and brucellosis infection in Marmota himalayana plague foci in the Altun Mountains on the Qinghai-Tibet Plateau.

The Altun Mountains are among the most active regions of Marmota himalayana plague foci of the Qinghai-Tibet Plateau where animal plague is prevalent, whereas only three human cases have been found since 1960. Animal husbandry is the main income for the local economy; brucellosis appears sometimes in animals and less often in humans. In this study, a retrospective investigation of plague and brucellosis seroprevalence among humans and animals was conducted to improve prevention and control measures for the two diseases. Animal and human sera were collected for routine surveillance from 2018 to 2021 and screened for plague and brucellosis. Yersinia pestis F1 antibody was preliminarily screened by the colloidal gold method at the monitoring site to identify previous infections with positive serology. Previous plague infection was found in 3.2% (14/432) of the studied human population having close contact with livestock, which indicates evidence of exposure to the Yersinia antigen (dead or live pathogenic materials) in the Altun Mountains. Seroprevalence of brucellosis was higher in camels (6.2%) and sheepdogs (1.8%) than in other livestock such as cattle and sheep, suggesting a possible transmission route from secondary host animals to humans.

Epidemiological Characteristics of Human and Animal Plague in Yunnan Province, China, 1950 to 2020.

This study analyzed the epidemiological characteristics of 3,464 human plague cases and the distribution pattern of 4,968 Yersinia pestis isolates from humans, hosts, and vector insects from 1950 to 2020 among two natural plague foci in Yunnan Province, China. These foci include the Rattus flavipectus plague focus of the Yunnan, Guangdong, and Fujian provinces and the Apodemus chevrieri-Eothenomys miletus plague focus of the highlands of northwestern Yunnan Province. The case fatality rate for plague in humans was 18.39% (637/3,464), and the total isolation rate of Y. pestis was 0.17% (4,968/2,975,288). Despite that the frequency of human cases declined rapidly, the animal plague fluctuated greatly, alternating between activity and inactivity in these foci. The tendency among human cases can be divided into 4 stages, 1950 to 1955, 1956 to 1989, 1990 to 2005, and 2006 to 2020. Bubonic plague accounted for the majority of cases in Yunnan, where pneumonic and septicemic plague rarely occurred. The natural plague foci have been in a relatively active state due to the stability of local ecology. Dense human population and frequent contact with host animals contribute to the high risk of human infection. This study systematically analyzed the epidemic pattern of human plague and the distribution characteristics of Y. pestis in the natural plague foci in Yunnan, providing a scientific basis for further development and adjustment of plague prevention and control strategies. IMPORTANCE Yunnan is the origin of the third plague pandemic. The analysis of human and animal plague characteristics of plague foci in Yunnan enlightens the prevention and control of the next plague pandemics. The plague characteristics of Yunnan show that human plague occurred when animal plague reached a certain scale, and strengthened surveillance of animal plague and reducing the density of host animals and transmission vectors contribute to the prevention and control of human plague outbreaks. The phenomenon of alternation between the resting period and active period of plague foci in Yunnan further proves the endogenous preservation mechanism of plague.

Plague Outbreak of a Marmota himalayana Family Emerging from Hibernation.

In April 2021, a plague outbreak was identified within one Marmota himalayana family shortly after emerging from hibernation, during plague surveillance in the M. himalayana plague foci of the Qinghai-Tibet Plateau. A total of five marmots were found dead of Yersinia pestis near the same burrow; one live marmot was positive of Y. pestis fraction 1 (F1) antibody. Comparative genome analysis shows that few single nucleotide polymorphisms were detected among the nine strains, indicating the same origin of the outbreak. The survived marmot shows a high titer of F1 antibody, higher than the mean titer of all marmots during the 2021 monitoring period (W = 391.00, Z = 2.81, p < 0.01). Marmots live with Y. pestis during hibernation when the pathogen is inhibited by hypothermia. But they wake up during or just after hibernation with body temperature rising to 37°C, when Y. pestis goes through optimal growth temperature, increases virulence, and causes death in marmots. A previous report has shown human plague cases caused by excavating marmots during winter; combined, this study shows the high risk of hibernation marmot carrying Y. pestis. This analysis provides new insights into the transmission of the highly virulent Y. pestis in M. himalayana plague foci and drives further effort upon plague control during hibernation.

First Case Report of Human Plague Caused by Excavation, Skinning, and Eating of a Hibernating Marmot (Marmota himalayana).

Introduction: The Qinghai-Tibet Plateau is considered the most plague-heavy region in China, and skinning and eating marmots (Marmota himalayana) are understood to be the main exposure factors to plague. Yersinia pestis is relatively inactive during marmots' hibernation period. However, this case report shows plague infection risk is not reduced but rather increased during the marmot hibernation period if plague exposure is not brought under control. Case Presentation: The patient was a 45-year-old man who presented with high fever, swelling of axillary lymph nodes, and existing hand wounds on his right side. Y. pestis was isolated from his blood and lymphatic fluid. Hence, the patient was diagnosed with a confirmed case of bubonic plague. Later, his condition progressed to septicemic plague. Plague exposure through wounds and delays in appropriate treatment might have contributed to plague progression. Conclusion: This case report reveals that excavating a hibernating marmot is a significant transmission route of plague. Plague prevention and control measures are priority needs during the marmot hibernation period.

A Lytic Yersina pestis Bacteriophage Obtained From the Bone Marrow of Marmota himalayana in a Plague-Focus Area in China.

A lytic Yersinia pestis phage vB_YpP-YepMm (also named YepMm for briefly) was first isolated from the bone marrow of a Marmota himalayana who died of natural causes on the Qinghai-Tibet plateau in China. Based on its morphologic (isometric hexagonal head and short non-contractile conical tail) and genomic features, we classified it as belonging to the Podoviridae family. At the MOI of 10, YepMm reached maximum titers; and the one-step growth curve showed that the incubation period of the phage was about 10 min, the rise phase was about 80 min, and the lysis amount of the phage during the lysis period of 80 min was about 187 PFU/cell. The genome of the bacteriophage YepMm had nucleotide-sequence similarity of 99.99% to that of the Y. pestis bacteriophage Yep-phi characterized previously. Analyses of the biological characters showed that YepMm has a short latent period, strong lysis, and a broader lysis spectrum. It could infect Y. pestis, highly pathogenic bioserotype 1B/O:8 Y. enterocolitica, as well as serotype O:1b Y. pseudotuberculosis-the ancestor of Y. pestis. It could be further developed as an important biocontrol agent in pathogenic Yersinia spp. infection.