The first reported cases of severe fever with thrombocytopenia syndrome virus from domestic sick camel to humans in China

ABSTRACT

Severe fever with thrombocytopenia syndrome (SFTS) is an emerging tick-borne disease with an increasing annual incidence rate. In this case report, we presented two patients infected with the SFTS virus, suggesting a potential direct transmission route from camels to humans through blood contact. Both patients developed symptoms after engaging in the slaughtering of one sick camel, while their family members living in the same environment or co-diners remained unaffected. Subsequent detection revealed a high viral load of SFTS virus, reaching 10¹⁰ viral RNA copies/ml, in the sample obtained from the sick camel. Metagenomic sequencing did not identify any other pathogens. The SFTS virus was successfully isolated from both patient and camel samples. The complete nucleotide sequences obtained from the infected patients demonstrated a remarkable 100% similarity to those found in the camel, and genetic evolution analysis classified the virus as genotype A. Additionally, partial sequences of the SFTS virus were identified in ticks captured from the camel rearing environment, however, these sequences showed only 95.9% similarity to those found in camel and humans. Furthermore, immunoglobulin M and immunoglobulin G antibodies were detected in serum samples collected from the patient. Our findings provide evidence that camel may serve as a competent reservoir for transmitting the SFTS virus to humans. Further in vitro investigations into SFTS virus infections in large animals are warranted to understand their role in viral maintenance and transmission.

KEYWORDS:

• Severe fever with thrombocytopenia syndrome
• camel to humans
• tick
• genotype A
• China

Introduction

Severe fever with thrombocytopenia syndrome (SFTS) is caused by Dabie bandavirus which belongs to the Bandavirus genus of the Phenuiviridae family, commonly known as SFTS virus (SFTSV) [1]. The virus is a single-stranded negative-sense RNA molecule and has a genome consisting of three segments (S, M, L). The identification of SFTS initially occurred in China in 2009 [2]. Subsequent reports have indicated its endemicity in several countries, including China [3], South Korea[4], Japan[5], Vietnam[6], and Myanmar[7]. From 2010 to 2019, a total of 13,824 SFTS cases were reported in mainland of China, with the nationwide average annual fatality rate reaching 5.2% [8]. In Japan and South Korea, the case fatality rates were higher at 35% and 16.3% respectively [9,10].

The most likely route of natural circulation for SFTSV is between ticks and certain animals, with transmission to humans occurring through tick bites [11]. Furthermore, direct contact with patient’s blood serves as an important mode of transmission, particularly in high endemic areas where clusters of SFTS cases have been observed [12].

By either way of transmission to humans, the incubation period of SFTS has been reported to range from 7 to 14 days (with an average of 9). The major clinical manifestations include high fever, fatigue, gastrointestinal symptoms, thrombocytopenia, and leukocytopenia [13]. Severe cases may progress to exhibit neurologic and haemorrhagic symptoms leading to multiple organ failure in the terminal stage. Notable clinical aspects of SFTS also include substantial elevation in serum levels of alanine aminotransferase, aspartate transaminase, lactate dehydrogenase, and Creatine Kinase. Serum viral load remains high in fatal cases but decreases in convalescent patients; this can serve as a prognostic marker associated with fatal outcomes [14]. Research on host animals has shown relatively low prevalence of SFTSV RNA (ranging from 1.7% to 5.3%) in animal sera [15], antibodies against SFTSV have been detected in various animal species, including cattle, goats, sheep, dogs, pigs, chickens, cats, rodents, and hedgehogs [16–20]. Although the majority of animals infected with SFTSV do not exhibit obvious symptoms, isolated and infrequent cases have been reported in Japan and South Korea where cats and dogs displayed clinical symptoms associated with SFTSV infections [21,22]. Direct transmission of the virus from animals to humans has only been reported for cats and dogs in Japan and South Korea [23–25], with no documented evidence supporting large animals as sources of SFTSV transmission to humans. In this study, we present two cases where humans in Beijing acquired an SFTSV infection from a sick camel. To establish the existence of this previously unknown camel-to-human transmission route for SFTSV, a comprehensive epidemiological investigation was conducted, along with viral isolation, whole-genome sequencing, and phylogenetic analyses. The results provide compelling evidence to support this novel transmission route.

Materials and methods

Identification of patients and epidemiological investigation

In September 2023, two male farmers in Beijing were admitted to the Beijing Municipal Infectious Disease Hospital due to intermittent fever. SFTS was suspected based on the initial clinical manifestations, and further real-time PCR tests confirmed infection with SFTSV. An epidemiological investigation was conducted to obtain their demographic information, medical history, living environment, history of animal contact, and tick bite history.

Serum samples from the two patients were collected at various time points after disease onset. To determine the potential source of infection, field investigations were carried out at the patients’ residences in Donglujiao village in Pinggu District. All companion animals, livestock, and poultry that had come into contact with the two patients were investigated and sampled. Given that both patients reported slaughtering a sick camel 4 or 5 days prior to disease onset, special efforts were made to collect tissue and blood specimens from the camel as well as environmental samples from areas where it was raised and slaughtered (including surface swabs, sewage samples, and dry feces samples). Ticks were collected through flagging in proximity to the camel’s habitat and around the patients’ homes. An investigation was performed on the family members of the patients to obtain epidemiological and clinical information, following guidelines outlined in “Technical Guidelines for the Prevention and Treatment of Severe Fever with Thrombocytopenia Syndrome (2010)” developed by the National Health and Family Planning Commission (NHFPC). Blood samples were obtained from family members who reported recent fever or influenza-like symptoms after illness onset in the two patients. According to the regulations and guidelines of the NHFPC of China, data collection from patients should be carried out as part of a routine surveillance and outbreak investigation and was therefore exempt from oversight by the institutional review board. All participating subjects signed consent forms approving their involvement in the investigation, sample collection, and data publication.

Virus isolation and identification

Blood samples from the patients and camel were processed for viral isolation. Briefly, the blood samples were centrifuged to obtain the serum, from which the virus was isolated. Briefly, Vero cells were cultured in monolayers in T25 flasks. After being washed twice with Hank’s solution, the cells were treated with 0.1 mL patient or camel serum diluted in Hank’s solution (1:10 dilution) at 37°C for 2 h. Subsequently, the cells were washed twice with 5 mL of sterile Hank’s solution and cultured in Dulbecco's Modified Eagle Medium (Gibco) containing 2% fetal calf serum (Gibco) supplemented with 100 U/ml penicillin (Sigma) and 100 mg/mL streptomycin (Sigma) in a 5% CO₂, 37°C incubator. The culture medium was refreshed every 7 days, and blind passages were performed three times to propagate the cells. The successful isolation of SFTSV was determined through quantitative reverse transcription PCR (qRT-PCR) and subsequently confirmed by immunofluorescent assay (IFA). Briefly, total RNA was purified from the supernatants of the cell cultures, followed by RT–PCR as previously described [26]. For IFA [27], the cells were fixed with cold acetone for 30 min, incubated with antibody-positive human serum at 37°C for 30 min, followed by secondary antibody incubation using goat anti-human IgG conjugated with FITC. Finally, the cells were observed using fluorescence microscopy (Nikon).

Molecular and serological test of SFTSV

The RNA was extracted from patient serum, camel kidney tissue, camel blood, and environmental samples, as well as the collected ticks. RT–PCR was performed using a Quantitative SFTSV RT–PCR Kit (Da’an Gen, Guangzhou, China) on the ABI 7500 system (Applied Biosystems, Carlsbad, CA, USA). To determine viremia levels in both patients and camel, median tissue culture infective dose (TCID50) values obtained from the RT–PCR results were used. Accurate quantification of the samples’ viral loads was achieved by employing a standard curve derived from known viral content (TCID50) standards provided in the reagent kits. This approach provides a more direct indication of viral RNA shedding in specimens. The presence of immunoglobulin (Ig)M and IgG specific to SFTSV was tested by performing an IFA on SFTSV-infected cells.

Sequencing and phylogenetic analysis

Viral nucleic acid-positive samples were used for whole-genome sequencing. Briefly, the Transcriptor First Strand cDNA Synthesis Kit (Roche) was employed for reverse transcription, followed by RT–PCR amplification of viral S, M, and L fragments. The primer sets used in this study were previously described [28], consisting of three pairs of primers designed to amplify the S fragment, seven pairs for the M fragment, and 12 pairs for the L fragment. Each amplification product had a length ranging from 500 bp to 700 bp with a 120-bp overlap sequence that covered the entire viral genome. Sequencing was performed bidirectionally on each PCR product and the resulting sequences were assembled using the SeqMan programme of DNAStar 7.0 software to generate the complete genomic sequence. The assembled sequences of the S, M, and L segments were subsequently submitted to GenBank.

In addition, full-length sequences of 36 SFTSV isolates from China, Japan, and the Republic of Korea were retrieved from GenBank representing all six known genotypes (A-F) of SFTSV [29]. MegaX software was employed for a comprehensive analysis aiming to determine the genotype of the isolated virus and analyze its genetic evolution. The neighbor-joining method with multiple alignments of the L, M, and S sequences was employed to construct a phylogenetic tree. The reliability of the results was estimated using the bootstrap method with 1,000 replications.

Next-generation sequencing

To exclude the possibility of other pathogens causing illness in the camels, we performed metagenomic sequencing of the camel samples. The RNA/DNA extracted from the camel blood sample was quantified using a Qubit 2.0 Fluorometer (Thermo Fisher Scientific, Waltham, MA, USA). The RNA was reverse-transcribed and then amplified using an ULSEN MicroSpectrum Kit (MicroFuture, Beijing, China). For library preparation and sequencing, we employed the Illumina Nextera XT Library Prep Kit (Illumina, San Diego, USA) followed by Illumina sequencing. The obtained reads data were compared against microbial databases using a commercial pipeline (CLC Genomic Workbench, Qiagen, Germany). The number of reads that matched certain pathogens was obtained, and the presence of possible pathogens was considered.

Results

Patient 1 was a 62-year-old farmer living with four family members, who were otherwise healthy in Pinggu District, Beijing. On September 16, 2023, he developed a high fever (38.5°C) accompanied by cephalalgia and myalgia. Initially, the patient self-administered “ibuprofen” which temporarily reduced the fever; however, the fever recurred within 6-8 h. By September 23, the patient’s conditions deteriorated; as fatigue and fever persisted with a body temperature of 39.7°C. Despite receiving antipyretic medication and supportive care at the local clinic, there was no improvement in symptoms, instead, they continued to worsen. Hematologic examination revealed leukocytopenia and thrombocytopenia, with decreased white blood cell (WBC) count of 2.2 × 10⁹/L and platelet (PLT) counts of 70 × 10⁹/L, respectively. On Day 8 of illness (September 24), the patient’s condition further deteriorated, exhibiting fever, nausea, diarrhea, and confusion along with cognitive impairment signs, such as delayed responses, impaired speech, as well as lip and limb tremors, leading to Pinggu District Hospital admission for comprehensive management. By day 10, the WBC count had decreased to 1.3 × 10⁹/L, and his PLT count dropped to 35 × 10⁹/L. Elevated levels of alanine aminotransferase, aspartate aminotransferase, and lactate dehydrogenase were also recorded (Table 1). On September 25, the patient was subsequently transferred to Beijing Municipal Infectious Disease Hospital.

Table 1. Sequential laboratory data for the two patients with SFTS over the clinical course.

	Patient 1						Patient 2
Days of disease onset /exposure to camel	9/14	10/15	12/17	14/ 19	16/ 21	18/ 23	10/14	11/15	13/ 17	15/ 19	17/ 21	19/ 23
RT-qPCR (Ct Value)	+ (24)	NT	+ (28)	NT	+ (33)	+ (37)	+ (26)	NT	+ (30)	NT	+ (34)	+ (38.5)
Viral load*	1.9 × 10^4	NT	5.2 × 10^2	NT	7.7	0.47	1.1 × 10^4	NT	2.4 × 10^2	NT	3.8	0.16
SFTS IgM	−	NT	+	NT	+	+	+	NT	+	NT	+	+
SFTS IgG	−	NT	−	NT	+	+	−	NT	−	NT	+	+
WBC (4-10 10^9/L)	1.3	5.56	8.57	8.46	8.73	7.05	1.4	2.51	3.07	2.85	3.69	3.7
Platelets (85-30 10^9/L)	35	52	51	80	157	248	54	53	46	84	179	262
ALT (9-50U/L)	49	74.1	74.2	66.7	46.5	40.1	108.4	121.6	138.1	149.7	124.8	79
AST (15-40U/L)	158	269.2	106.8	35	28.7	29.1	326.9	364	170.6	123.4	58.1	31.5
CK (26-196U/L)	730	870.6	201	76.8	280.1	214.4	3232	2395.7	762.2	NT	100	74.6
LDH (135-225U/L)	868	1661.4	1074	485.3	360.9	300.7	1310.4	1682.2	984.3	NT	506.8	385.2

Abbreviations: SFTS, severe fever with thrombocytopenia syndrome; WBC, white blood cells; RBC, red blood cells; AST, aspartate aminotransferase; ALT, alanine aminotransferase; LDH, lactate dehydrogenase; CK, Creatine Kinase; NT, not tested.

*The SFTSV viral load was measured as TCID50/ml serum.

The second patient, a 52-year-old male farmer, resided with his four-family members in the same village as Patient 1; however, there were no interactions between the two patients in their daily lives. On September 15, 2023, he presented with intermittent fever peaking at 38.8°C, accompanied by chills and shivering. The patient also reported symptoms of dizziness, headaches, a sensation of walking on cotton, myalgia, xerostomia, and pharyngalgia. Despite self-administering antipyretic medication, his symptoms did not improve. Diarrhea onset occurred the following day with a frequency of 4–5 times per day, along with persistent febrile illness and fainting episodes. The patient sought medical care at Pinggu District Hospital on September 23, where leukopenia (white blood cell count of 1.8 × 10⁹/L) and thrombocytopenia (platelet count of 107 × 10⁹/L) were noted. Rotavirus testing yielded negative results. The patient was transferred to Beijing Municipal Infectious Disease Hospital on September 25, where he was recorded as having a white blood cell count of 2.1 × 10⁹/L and a platelet count of 68 × 10⁹/L (Figure 1).

Figure 1. Dynamics of laboratory indicators for two patients. a White blood cell (WBC) and platelet (PLT) counts; b alanine aminotransferase (ALT) and aspartate aminotransferase (AST); c creatine kinase (CK) and lactate dehydrogenase (LDH); and viral load are shown.

Both patients recovered after receiving favipiravir antiviral treatment and supportive care for two weeks. They were discharged on October 8, 22 and 23 days after disease onset, respectively.

Epidemiological investigations

Epidemiological investigation revealed that Patient 1 had raised a single camel in his backyard for six months. The patient recalled the camel was kept in captivity and had not moved freely outside the yard. In September, the camel exhibited symptoms such as decreased appetite, disrupted rumination, less activity than usual, and laboured breathing. Subsequently, its condition deteriorated and it was deemed terminally ill 7 days later. Consequently, Patient 1 slaughtered the camel, with assistance from Patient 2, using a machete in Patient 1’s backyard, without employing any protective measures. Neither of the patients were involved in breeding domesticated animals within their household. Both patients denied traveling outside of Beijing, having a history of tick bites, recent visits to poultry markets, or contact with animals other than the aforementioned camel. We interviewed eight close-contact family members (four family members of Patient 1 and four of Patient 2) who resided with them; none reported experiencing an illness resembling SFTS within 14 days before or after the current episode of the two patients. During the investigation, we used the flagging method to capture 30 tick larvae from the farmyard. The density of ticks, estimated at approximately 10 ticks per flag per hour, indicated a moderate infestation.

SFTSV RNA and antibody detection

The molecular testing of the three animal samples and six environmental samples resulted in eight positive findings for SFTSV, including one sample each from the meat, kidney, and blood from the camel; three swabs of dried bloodstains on the ground; and one swab of the slaughter knife, which had been collected at 17 days after the camel butchering. Notably, the specimen obtained from the camel exhibited a relatively high SFTS viral load (Figure S1), with a cycle threshold (Ct) value of 12, which corresponded to 2.7 × 10⁷ TCID50/ml or 1.07 × 10¹⁰ viral RNA copies/ml [30], approximately 1,000 times higher than that found in serum samples from patients.

The level of SFTSV viremia was evaluated as 1.9 × 10⁴ TCID50/ml for Patient 1 and 1.1 × 10⁴ TCID50/ml for Patient 2 upon admission into the Beijing Municipal Infectious Hospital. Their levels then showed continuous declines after receiving antiviral treatment during hospitalization. For Patient 1, Ct values for SFTSV increased from 24 on day 9–37 on day 18, corresponding to a decrease in viral load from 1.9 × 10⁴ TCID50/ml to 0.47 TCID50/ml. For Patient 2, the Ct value increased from 26 on day 10–38.5 on day 19, when it exceeded the lower limit of detection, and the viral load decreased from 1.1 × 10⁴ TCID50/ml to 0.16, suggesting the possible viral clearance (Table 1). The 30 captured ticks were pooled together for analysis due to their small size, showing positive qRT-PCR results for SFTSV. Serum samples were collected from the patients 14, 17, 21, and 23 days after exposure. IgM antibodies were detected in Patient 1’s day 17 sample and persisted till day 23. Patient 2’s sample on day 14 showed detectable IgM antibodies which remained positive till day 23. IgG antibodies were detected from day 21 after exposure in both patients’ serum samples.

Virus isolation

Three strains of SFTSV were successfully isolated from the two patients and the serum sample of the camel, which were designated as BJ2023-PG-003, BJ2023-PG-004, and BJ2023-PG-Camel, respectively. By employing qRT-PCR, the presence of SFTS RNA was detected in the cell supernatants from the inoculation passages of the camel and serum samples of both patients. Specifically, a positive result for the SFTS antigen was obtained during the first passage of camel serum inoculation, while a positive result for the antigen was observed during the second passage of patient sera inoculations (Figure 2).

Figure 2. SFTSV grown in Vero cells and detected with immunofluorescence assay. A, Camel; B, Patient 1; C, Patient 2; D, Mock. In the test, the primary antibody was SFTS-infected human serum. Goat anti-human IgG conjugated with FITC was served as the secondary antibody. Green fluorescence indicates positive staining; red cells represent negative cells.

Phylogenetic analysis

The complete genome sequences were successfully obtained from the three strains, demonstrating 100% sequence identity among them. The sequences of the S, M, and L fragments were deposited in the NCBI database with accession numbers OR679084–OR679093. The L segment of the current isolates showed 99.4% similarity to AHZ/China/2011 from Anhui province (JQ670929), while the M segment exhibited 99.32% similarity to 18-China_Henan-124 from Henan province (MN10154), and the S segment displayed 99.54% similarity to 18-China_Henan-74 from Henan province (MN510307). Two partial sequences (606 and 563 bp) from the M segment were obtained from ticks, both identical to those obtained from the camel. The partial sequences from the L fragment (636 bp), however, only showed 95.9% similarity to that obtained from the camel. Phylogenetic analyses using complete full-length sequences of the isolated strain and previously identified SFTSV strains revealed that all current stains clustered together with genotype A (Figure 3), which included SFTSV isolated from various geographic locations in China, such as Henan, Hubei, Anhui, Jiangsu, Zhejiang, and Liaoning provinces in China, as well as South Korea.

Figure 3. Phylogenetic analysis of complete nucleotide sequences of SFTSV strains. We used an NJ method, and the numbers on the branches indicate bootstrap percentages based on 1,000 replicates. The scale bar indicates the number of nucleotide substitutions per site. The phylogenetic branches were supported with greater than 70% bootstrap values. The patient- and camel-derived SFTSV strains analyzed in this study are indicated by the red closed triangles. NJ, Neighbour-joining algorithm; SFTSV, severe fever with thrombocytopenia syndrome virus.

Next-generation sequencing

The blood specimen obtained from the camel was subjected to comprehensive metagenomic sequencing analysis. Remarkably, no additional pathogenic bacteria or viruses were detected, suggesting that the blood sample was devoid of any other potential infectious agents than SFTSV.

Discussion

The first report of human SFTS cases in China was documented in 2009, primarily in rural areas of Henan, Shandong, Anhui, and other central provinces. However, there has been a significant increase in its geographical distribution in recent years, with new natural foci continuously emerging [8]. This expansion has led to a 10-fold increase in annual case numbers from 2010 to 2023. It is worth noting that cases have also been reported within the expanded range of urban areas The main contributing factor to the spread of SFTS in China is the expanding population size and geographical range of Haemaphysalis longicornis, the primary tick vector responsible for the transmission of SFTSV [11], which has even established its population within Beijing. Previously, only one local SFTS case had been reported in Beijing, where the individual was infected via tick bites [31]. However, in this study, we present two unusual cases in another district of Beijing. These cases suggest a novel transmission pathway for SFTSV, as the individuals might have acquired the infection through exposure to an SFTSV-infected camel, rather than tick bites. Epidemiological investigations conducted in China have revealed a high seroprevalence of SFTSV among domestic animals, despite the absence of apparent clinical signs or substantial induced viremia [16,17]. Meanwhile, companion animals such as cats and dogs, have been reported as sources of human infections via bites [23] or close contact [24,25]. While extensively documented in Japan and South Korea, this phenomenon has not yet been reported in China.

In the current study, we have acquired anecdotal evidence suggesting a potential occurrence of a fatal disease in a camel with SFTSV infection, which may have acquired the infection through tick bites. Due to the fact that the camel had been slaughtered prior to the investigation, we were unable to retrieve any ticks that may have been attached to the camel. Therefore, confirmation of the relationship between ticks and the camel remains elusive. Nevertheless, we successfully obtained positive results for SFTSV from tick larvae collected in its rearing environment, exhibiting an identical partial M sequence as those obtained from both camel and patients. However, there was only 95.9% similarity between these sequences and those acquired from both camel and patients for the L fragment (636 bp). This discrepancy could be explained by the existence of multiple SFTSV genotypes in the captured ticks, therefore when the tick larvae were pooled for SFTSV detection, L and M segments that belonged to different tick hosts might be amplified.

We thus propose that patients were infected via contact with the SFTSV-infected camel, as exposure to blood or other body fluids containing the virus might serve as a predominant mode of human-to-human transmission. In this case, high-viremia camel blood is likely to act as a direct source of transmission to humans when no personal protective equipment was used. This notion was corroborated by the identical genome sequences obtained from both human patients and the camel; the detection of a high viral load in frozen camel meat even after 17 days, and the onset of symptoms in patients coinciding with the incubation period following disease onset in camels. Other epidemiological findings also support this hypothesis: (1) No reports of tick bites or visible scars on patients; (2) The extended period during which camels had limited activity and no contact with other animals except for possible tick bites; (3) The two patients had minimal interactions in their daily lives except for participating in current camel slaughtering activities, while their family members who lived in the same environment remained unaffected.

Our findings further suggest the coexistence of multiple genotypes of SFTSV in Pinggu District. As the ticks were detected in mixed pools, the variations in sequence similarity between the L and M segments could indicate the circulation of different genotypes of SFTSV within the tick population in Beijing. Previous studies have classified SFTSV into six genotypes (A–F) in China with genotypes A and E being widely distributed across all epidemic areas [29]. It is common for multiple genotypes of the virus to coexist within the same epidemic area. In Beijing, the first local case reported in Mentougou District belonged to genotype B [32]. Ticks carrying genotype E SFTSV have been found in Shunyi District [33]. The presence of diverse genotypes contrasts with the sporadic case reports, suggesting that SFTSV infections among humans, vectors, or animals may be underreported in Beijing. Therefore we call for enhanced surveillance efforts in Beijing to attain a comprehensive understanding of the current epidemiological situation. Additionally, further investigation is needed to determine the source of SFTSV in ticks captured in Pinggu District. One hypothesis proposes that migratory birds might have contributed to the dissemination of ticks carrying SFTSV [34]. It is possible that a stable circulation of multiple-genotype of SFTSV has been established within the tick population by infesting domestic or wild animals, which have become more abundant in recent years in the suburban area of Beijing, further facilitating the spread of the virus into human residential areas where the infected camel was kept (Figure 4).

Figure 4. Probable sources of infection.

This study has several limitations. The unavailability of tick samples obtained from camels poses a constraint on gathering additional evidence. Future laboratory studies, including the analysis of SFTSV isolates from camels, with a specific focus on the receptor-binding domains (RBDs), may provide valuable insights. Additionally, conducting relevant animal experiments targeting this specific viral strain could contribute to a more comprehensive understanding of the disease.

In summary, this study has highlighted the potential transmission risk posed by another animal host of SFTSV. The camel was found to harbour high a viral load, indicating its probable capacity to serve as a competent reservoir for the transmission of SFTSV to humans. Further, in vitro investigations into SFTSV infections in large animals, as well as their role in viral maintenance and transmission are warranted. It is imperative that China implements comprehensive tick control measures for domestic animals and develop effective strategies to mitigate the risk of animal-to-human transmission.

Disclosure statement

No potential conflict of interest was reported by the author(s).

Additional information

Funding

This work was supported by National Key R&D Program of China [grant number: 2021ZD0114103] and National Natural Science Foundation of China [grand number: 81825019].